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Review

Tumor Microenvironment Regulation and Cancer Targeting Therapy Based on Nanoparticles

1
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China
2
Key Laboratory of Green Process and Engineering, State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
3
University of Chinese Academy of Sciences, Beijing 100049, China
4
Department of Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
*
Author to whom correspondence should be addressed.
J. Funct. Biomater. 2023, 14(3), 136; https://doi.org/10.3390/jfb14030136
Submission received: 7 January 2023 / Revised: 24 February 2023 / Accepted: 25 February 2023 / Published: 28 February 2023

Abstract

:
Although we have made remarkable achievements in cancer awareness and medical technology, there are still tremendous increases in cancer incidence and mortality. However, most anti-tumor strategies, including immunotherapy, show low efficiency in clinical application. More and more evidence suggest that this low efficacy may be closely related to the immunosuppression of the tumor microenvironment (TME). The TME plays a significant role in tumorigenesis, development, and metastasis. Therefore, it is necessary to regulate the TME during antitumor therapy. Several strategies are developing to regulate the TME as inhibiting tumor angiogenesis, reversing tumor associated macrophage (TAM) phenotype, removing T cell immunosuppression, and so on. Among them, nanotechnology shows great potential for delivering regulators into TME, which further enhance the antitumor therapy efficacy. Properly designed nanomaterials can carry regulators and/or therapeutic agents to eligible locations or cells to trigger specific immune response and further kill tumor cells. Specifically, the designed nanoparticles could not only directly reverse the primary TME immunosuppression, but also induce effective systemic immune response, which would prevent niche formation before metastasis and inhibit tumor recurrence. In this review, we summarized the development of nanoparticles (NPs) for anti-cancer therapy, TME regulation, and tumor metastasis inhibition. We also discussed the prospect and potential of nanocarriers for cancer therapy.

Graphical Abstract

1. Introduction

The data from the International Agency for Research on Cancer show that cancer is a major disease with the highest morbidity and mortality worldwide [1]. Common clinical anti-cancer treatments, such as radiotherapy, chemotherapy, surgery, and other targeted cancer treatments, have many shortcomings including multiple complications, high rate of recurrence and metastasis, off-target effect, easy drug resistance, and serious toxicity, which greatly reduce the patients’ quality of life [2,3,4,5]. Cancer immunotherapy is emerging as the fifth anti-cancer treatment strategy. The treatment activates the host immune system for recognizing and destroying cancer cells in an antigen-specific manner [6]. In recent years, some immunotherapy, such as the programmed cell death protein 1(PD-1), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and the chimeric antigen receptors T cells (CAR-T), have achieved promising clinical therapeutic effects in cancer. However, overall treatment response rates still remain low (<20%), which is far below expectations if cancer types are taken into account as a whole [7,8,9].
Increasing evidence indicates that the complexity of TME results in poor treatment effectiveness of cancer immunotherapy, chemotherapy, and targeted therapy [10,11,12]. The immunosuppressive microenvironment supports the occurrence and development of the tumor, which leads to immune escape of tumor cells [13]. The tumor microenvironment (TME) includes diverse immunosuppressive factors, such as incapacitated immunostimulatory cells (e.g., dendritic cells (DCs), T helper (Th) cells, cytotoxic T lymphocytes (CTLs), M1-like tumor-associated macrophages (M1-like TAMs), natural killer (NK) cells), activated immunosuppressive cells (e.g., myeloid-derived suppressor cells (MDSCs), M2-like tumor-associated macrophages (M2-like TAMs), regulatory T cells (Treg), cancer-associated fibroblasts (CAFs), the tumor vasculature, extracellular matrix (ECM), hypoxia, and low pH [14,15,16,17,18]. The above immunosuppressive factors contribute to a variety of mechanisms for tumor therapy inhibition in tumor-associated macrophages (TAMs), which further promote the occurrence and development of cancer [19,20]. Therefore, it is necessary for improving anti-cancer treatment through regulation of TME immunosuppression.
Nanomaterials are widely employed for anti-tumor treatment and TME regulation [21,22,23]. The nanomaterials with modulators such as multifunctional platforms can effectively eliminate the primary cancer, inhibit the distal metastasis, and prevent cancer recurrence [22,24,25,26]. Nanomaterials mainly regulate TME through the following four mechanisms: (i). Promote the immunogenicity of cancer antigens [27,28,29,30,31]; (ii). Activate disabled immune cells [32,33,34,35,36]; (iii). Reverse immunosuppressive cells [14,37,38,39,40]; (iv). Improve TME microenvironment (for hypoxia, low pH, vasculature, etc.) [41,42,43,44]. The application of nanomaterials in unilateral cancer treatment (e.g., chemotherapy, immunotherapy) has been reviewed [12,45,46,47]. In this paper, we highlight the various types of nanoparticles and their applications as antitumor agents and in regulating the TME. In addition, the clinical application outlook and challenges of these nanoparticles are also discussed.

2. The Nanocarriers for Cancer Targeting Therapy

Nanocarriers for cancer therapy can be classified into many types, including inorganic nanoparticles (inorganic NPs), liposome, polymer NPs, biomimetic NPs, and natural NPs (Table 1). They have achieved good treatment effects by stimulating different anticancer mechanisms through delivering of delivery of various therapeutic agents in vivo. Some of them have entered different clinical phases and even been approved as effective drugs by the US Food and Drug Administration (FDA). Most are based on liposome and polymer nanocarriers, and some metal nanocarriers are also approved for imaging diagnosis in clinical practice.

2.1. Inorganic NPs

The inorganic nanoparticles include gold NPs, silver NPs, and silica NPs, etc., and among them, gold nanoparticles were the first used for anti-tumor therapy [48,49,90,91]. However, despite concerns for the unavoidable biological safety in vivo, most gold/silver nanoparticles are approved for imaging and diagnosis of cancer in clinical application [92,93]. The biological toxicity of AuNP/Silver NP mainly depends on their physical properties and surface chemical toxicity [94]. In recent years, green surface modification was applied for their biosafety improvement (Figure 1) [48,49,95]. For example, Pandey’s team designed gold nanocages coating with a poly(ethylene glycol) monolayer. The photosensitizer was noncovalently encapsulated in the gold nanocages. These gold nanocages achieved drug accumulation in the tumor site and significantly inhibited the tumor growth with almost no toxicity and phenotypical changes in mice [48]. Park’s team synthesized silver core/shell nanoparticles modified with polyethylene glycol bovine serum albumin (BSA), which has a high indocyanine green (ICG) loading efficiency. The NPs could accumulate at the tumor site. After laser irradiation, the tumor surface temperature rose to 50 ℃ (required for light ablation), the melanoma growth was successfully inhibited, and no obvious systemic toxicity was observed [96]. Previously, a variety of medicinal plant extracts were used to synthesize stable gold or silver NPs with multiple functions as antioxidant, antibacterial, anti-tumor, catalytic, and other biological activities [97,98,99,100,101,102,103]. This might be an effective strategy to promote approval of metal NPs for clinical tumor treatment in the future.
The application of mesoporous silica nanoparticles (MSNPs) in the biological field successfully demonstrated its advantages of good biocompatibility, high specific surface area and pore volume, allowing large drug loading, and easy chemical modification [104,105,106]. Kumar’s team fabricated folate or N-acetylglucosamine functionalized mesoporous silica NPs encapsulating doxorubicin (DOX-FA-MSNPs or DOX-NAG-MSNPs) for targeted breast cancer therapy [107]. These NPs greatly enhanced the cellular internalization and drug cytotoxicity, which showed little toxicity to normal cells. Engineered MSNPs have widely been employed for cancer drug delivery or imaging. In these systems, many types of molecules and therapeutic agents could be loaded into the nano porous structure or connected onto the surface using different linkers. In any case, controllable diameter, porosity, structure, or chemical composition were combined with selectable properties (e.g., pH, optical, thermal, optical, or magnetic stimulation) for molecular recognition and targeting treatment.

2.2. Lipid Nanocarriers

Liposomes (LPs) are composed of monolayer/multilayer amphiphilic membranes of natural or synthetic lipids [108]. LPs can load hydrophilic drugs in the water core and hydrophobic agents in the lipid bilayer, which makes them flexible and excellent delivery vehicles [109]. LPs are one of the earliest nanoplatforms used in drug delivery systems to carry various active ingredients for cancer treatment. Some liposomal formulations have been approved for clinical trial [57,62,109]. Currently, some LPs loading doxorubicin and paclitaxel which show better treatment for metastatic ovarian cancer and breast cancer in clinical practice have been approved by the FDA [110]. The liposomal nanocarriers could also improve the bioavailability and pharmacodynamics of drugs with poor solubility; however, the lower stability and uncontrollable drug release behavior in vivo affected their wide applications in clinical practice. Some targeting molecular modified liposomal nanocarriers have been designed for precise anti-cancer therapy (Figure 2) [111,112,113,114,115,116,117,118]. For example, Li’s team described a liposome carrier, namely folate (FA) modified liposome (FA-LP) NPs, which could co-deliver erastin and (metallothionein 1D) MT1DP to the cancer location. These LPs could sensitize erastin-induced ferroptosis, decrease cell GSH level, and increase lipid reactive oxygen species (ROS), synergistically inhibiting lung cancer cell growth [117]. The dual targeting strategy might also contribute to promoting LPs’ ability to target tumor cells. Octreotide-modified magnetic liposomes (OMlips) were used for oleanolic acid (OA) loading to form OA-Olips. The LPs exhibited better antitumor effect with little biotoxicity [116]. This kind of targeted molecule and magnetic field-mediated dual-targeted nano-carrier shows great clinical application potential. It was well known that drug resistance at tumor sites are a great obstacle in tumor therapy [112]. It was reported that direct targeting mitochondria is an effective strategy that has been developed in recent years [112,113,118]. Hu’s team developed liposomes with mitochondria target ability for doxorubicin loading from a berberine derivative, which not only increased the drug distribution in tumor, but also achieved better treatment efficiency in tumor-bearing mice with drug resistance [111].
In conclusion, although LP nano carriers have been widely studied because of their broad application prospects, they still have limitations including high cost, poor stability in vivo, weak organelle targeting capacity, and easy elimination by phagocytes [112,119,120,121]. Therefore, the development of more accurately targeted and stable liposomes still requires continuous efforts.

2.3. Polymer Nanocarriers

Polymer nanocarriers are widely used in anti-tumor’s agent delivery because of their excellent properties, such as biodegradability, biocompatibility, colloidal stability, low inflammation and immunogenicity, small size, and functionalized surface [122]. However, the polymer nanocarriers still remained uncontrolled in bioavailability and drug release at the tumor site. More and more polymer nanocarriers with the capacity of targeting and stimuli-response were designed for cancer therapy [123,124,125,126,127]. Enhanced permeability and retention (EPR), ligand receptor, polypeptide-mediated tumor targeting and pH, enzyme, hypoxia, and light-response are often considered in the design of nanocarriers (Figure 3). For example, He’s group designed a method to target tumor sites and pH-responsive polymer nano micelles with zwitterionic segments, employed for doxorubicin (DOX) trapping in the hydrophobic layer. The nano micelles showed smaller sizes and high stability in the system circulation and continued to release drugs in the low pH environment via EPR effect-mediated tumor targeting [124,125]. In addition, Hou’s team designed a dual-responsive polymeric nanoparticles, using triethylamine (TEA) as an acid binder; hexachlorocyclic-triphosphonitrile (HCCP) derived cysteine derivatives (CysM) oligomer was polymerized with DOX. Nanoparticles can target the tumor site via the EPR effect and respond to pH and glutathione for releasing an anti-cancer agent. The NPs show the stability of long circulation in blood circulation, but the response to low pH acidic environment in TME makes the drug release rapidly [128]. In addition, a polymeric indoleamine-(2,3)-dioxygenase (IDO) inhibitor based on the poly(ethylene glycol)-b-poly(L-tyrosine-co-1-methyl-D-tryptophan) copolymer (PEG-b-P(Tyr-co-1-MT)) was developed for facile trident cancer immunotherapy [129]. The polymeric IDO inhibitor was modified by Cyclo (Arg–Gly–Asp–D–Tyr–Lys) peptide (cRGD), which can bind to αvβ3 intergrin for targeting tumor cells. Moreover, the polymeric IDO inhibitor can delay the metabolism of l-tryptophan (TRP) to L-kynurenine (KYN) in cancer cells due to the degradation of enzyme responses. In melanoma-bearing mice, DOX in drug-loaded nanoparticles significantly increased matured DCs, CD8+ T cells, IFN-γ, and TNF-α, while reducing Treg cells and downregulating PD-L1 expression; this resulted in the improvement of the TME, suppression of tumor, and prolongation of the survival rate.
Previously, in order to improve the reaction rate and make the drug completely released to the target site, the dual response nanocarriers have been developed to respond to the combination of two signals (e.g., pH/temperature, pH/redox, and photo/temperature) [129,130,131,132]. Therefore, these novel double response nanocarriers have been proved to be anti-cancer drug delivery platforms that can be used for drug control release and targeting of tumor sites, which has a very favorable prospect for the treatment of solid tumors.

2.4. Hybrid Nanocarriers

Single-material nano delivery systems are limited to further research and clinical anti-tumor applications due to their inevitable defects, such as low biosafety of inorganic nanoparticles, high cost of liposome nanoparticles, poor targeting, and low bioavailability of polymer nanoparticles [92,93,120,121,125,126]. To solve these problems, a hybrid nanocarrier was developed for delivering anti-tumor therapeutic agents. The nano hybrid system is a nanocarrier that combines organic or inorganic nanomaterials and biological macromolecules into a single composite material (Figure 4). The combination of different nanomaterials can not only make the hybrid nanocarriers show better biosafety and more stable targeting, but also improve the delivery efficiency and bioavailability of drugs [133,134,135,136]. There have many reports about the use of hybrid NPs in cancer detection and treatment. There are some hybrid NPs for clinical diagnosis of cancer, including hybrid magnetic silicon dioxide NPs [137] and hybrid supermagnetic iron oxide NPs (SPIONS) [138,139,140,141]. Some hybrid NPs are used for cancer treatment, such as lipid coated polymers [142,143] and hybrid NPs coupled with genes [144].
One of the reasons why inorganic nanoparticles are mainly used in clinical diagnosis and imaging, but cannot be used in cancer treatment, is due to the lack of surface active groups and difficult surface modification, leading to poor targeting and serious liver toxicity [48,90,91]. However, photothermal effects are a major advantage of inorganic nanoparticles for cancer therapy, while the easy surface modification is the advantage of liposomes or polymer NPs. Therefore, combining the advantages of the two to construct hybrid nanocarriers can not only improve the targeting ability of nanocarriers, but also increase the anti-tumor effect of drugs. For example, Elhabak’ team developed a trastuzumab (TZB) surface modified poly(lactic-co-glycolic) acid (PLGA), circulating NPs that co-encapsulated magnolol (Mag) and gold NPs [139]. The optimized NPs have small particle sizes and high encapsulation efficiency. The surface modified NPs with TZB can target breast cancer due to the over expression of human epidermal growth factor-2 (HER2). The gold NPs and DOX encapsulated in PLGA NPs and DOX showed their photothermal effects and cytotoxicity, respectively, resulting in the multifunctional anti-breast cancer effect.
Lipid–polymer hybrid NPs are core shell nanoparticle structures comprising polymer cores and lipid/lipid polyethylene glycol (PEG) shells; these hybrids combine physical stability of polymeric nanoparticles and biocompatibility of liposomes. The development of lipid–polymer hybrid NPs broke the limits of single drug delivery and single function design for anticancer therapy. It not only delivers genetic materials, vaccines, and diagnostic imaging agents, but also deliver dual-drugs and targeting design [64]. Fraix et al. reported a lipid–polymer hybrid NP that delivers nitric oxide (NO) and DOX under visible light control [145]. They designed the hybrid nanosystem with DOX entrapped in the PLGA core and a NO photodonor (NOPD) in the phospholipid shell to avoid their mutual interaction. The release of NO inhibits the efflux transporters mostly responsible for DOX cellular extrusion, increasing DOX uptake by cells, and thus enhancing its antitumor activity.
In conclusion, combining multimodal components in a single hybrid NP allows the structural and functional properties of the resulting NPs to be adjusted in the desired way. The hybrid NPs can enhance their anti-tumor functional properties, and have advantages such as lower cost, simple preparation, good biological safety, precise targeting, controlled drug release, and environmentally responsive drug release, making them more suitable for clinical application.

2.5. Biomimetic and Natural Nanocarriers

Nanoparticles (NPs) are becoming more and more common in anti-tumor drug delivery research because they have significant advantages in anti-tumor efficacy and system safety compared with current clinical treatment and diagnosis models [67,69,106]. However, due to its non-specific interaction with phagocytes in vivo during delivery, its clinical application is unsatisfactory [14,25,146]. The retention of NPs by reticuloendothelial system in blood circulation is one of the main obstacles that almost all platforms must overcome. In order to reduce the non-specific interception of NPs, the addition of specific-targeted modification can achieve targeted delivery of NPs, enabling drugs to accumulate at specific sites, which is also an effective strategy to improve drug efficacy of anti-tumor agents. Therefore, biomimetic nanocarriers or natural nanocarriers, an emerging nanotechnology, were previously developed [147,148,149,150]. As the basic unit of biology, cells have a wide range of functions, including the ability to interact with the surrounding environment. They can decrease nonspecific interactions while increase specific targeting (Figure 5) [150,151,152,153,154]. Since 2011, cell membrane coating technology has been developed, for example, in coating the whole red blood cell (RBC) membrane on the surface of NPs [155]. They reported a natural bionic method of particle functionalization, which endows NPs with the function of long cycle delivery by wrapping natural RBC on the surface of biodegradable polymeric NPs. The in vivo results showed that the erythrocyte-mimicking NPs revealed superior circulation than particles without RBC. In 2018, by coating a cancer cell membrane (CCM) on the surface of SPIO@DOX-ICG (superparamagnetic iron oxide @DOX-ICG) nanoparticles, the researchers designed a bio-inspired biomimetic nano system that combines chemotherapy, hyperthermia, and radiation to achieve precise cancer treatment [156]. CCM retains tumor adhesion molecules and surface antigens, making the nano system have tumor homing ability and high biocompatibility. Nano systems can target tumor sites and achieve synergistic anti-cancer effects after systematic administration, without systemic toxic and side effects. Research reported that macrophage, neutrophils, T-cell, platelets, and cancer can all be used as biomimetic materials for coating nanoparticles, which play different targeting delivery and anti-tumor functions [155,156,157,158,159]. Extracellular vehicles (EVs) are also a very safe bionic carrier for drug targeting delivery which can pass through various obstacles without any side effects [158,160,161]. In 2019, Zhu’s team confirmed the anti-glioblastoma (GBM) effect of embryonic stem cells (ESCs) exosome. They then prepared cRGD-modified and paclitaxel (PTX)-loaded ESC-exosomes [162]. The in vitro/in vivo results showed that natural nanocarriers significantly improve the anti-tumor effects of PTX in GBM via an enhanced targeting rate.
In conclusion, biomimetic NPs are a new type of nanocarrier combining the advantages of natural and artificial nanomaterials. Nanoparticles wrapped in cell membranes essentially mimic the characteristics of source cells, giving them a wide range of functions such as long circulation and disease related targeting. Over time, the effectiveness of the cell membrane coating method will undoubtedly expand; there is an inestimable potential for future anti-tumor clinical applications.

3. Nanocarriers for TME Regulation and Cancer Therapy

The TME is a highly complex environment that surrounds tumors [163]. More and more evidence shows that TME plays an essential role in controlling tumor occurrence, metastasis, and drug resistance [14,18,72,164].
The tumor microenvironment includes the tissue and cellular population surrounding the tumor cells, such as immune cells, endothelial cells, fibroblasts, neurons, and others. These tissues and cellular populations interact with tumor cells, forming a network of cell-to-cell and cell-to-matrix interactions, known as the tumor microenvironment [165]. At the same time, the pH value, the degree of oxygen enrichment, and the redox condition in the tumor site are significantly different from the normal tissue site due to the influence of tumor cell proliferation. The abnormal cell survival conditions further inhibit the activity of immune cells in the tumor site and promote the proliferation and migration of tumor cells [166].
The complexity of TME limits anti-tumor treatment [12,167,168,169]. Therefore, overcoming TME barriers is essential for the deep delivery of therapeutic drugs and treatment effects. Regulating or reprogramming immunosuppressive TME plays important role in cancer therapy.
Previously, nanomaterials with TME as a target have been widely employed for anticancer drugs delivery to directly regulate the TME, which have achieved promising results [12,164,168]. There are certain ways to reprogram the TME through nanoparticles, such as (i) NPs for destroying extracellular matrix (ECM); (ii) NPs for activating immunostimulatory cells; and (iii) NPs for regulating immunosuppressive factors (Figure 6). In addition, the tumor microenvironment can be improved by adjusting the pH value, oxygen content, and redox environment of the tumor site.

3.1. Nanocarriers for Regulating ECM

The extracellular matrix (ECM) of TME is a network of collagen and hyaluronic acid which contains tumor growth factors, anti-inflammatory cytokines, and the tumor vascular system [170,171,172]. In solid tumors, the ECM is considered as a protective chamber that provides a safe environment for the occurrence and development of malignant tumors. Integrin, which transmits information with ECM to inhibit some immune cells and fibroblast’s function, is highly expressed on tumor cells and vascular endothelial cells [173,174]. Furthermore, the dense ECM forms an environment with high-pressure, greatly reducing the deep penetration and diffusion of anti-cancer drugs to weaken the anti-cancer treatment effect [175,176]. Destroying the ECM is a first effective strategy to diminish the barriers of TME (Figure 6) [167,168,172,177,178].
In order to overcome the barrier from ECM, two kinds of nanoparticles were used to destroy the tumor protective effect of ECM: (i) directly destroy the composition of ECM by using collagen nanoparticles; (ii) downregulate the substance expression in the ECM by using enzyme-carrying nanoparticles. For example, Zhou’s team reported NPs with the capacity of degrading hyaluronic acid; they loaded recombinant human hyaluronidase PH20 (rHuPH20) on the surface of PLGA-PEG NPs, and then, modified it with relatively low-density PEG layer to reduce rHuPH20 exposure and prevent it from being removed by macrophages [179]. The facile surface modification reduced TAF activity (an important component of tumor ECM synthesis and remodeling), increased the accumulation of these NPs in 4T1-bearing mice, and inhibited the development of invasive 4T1 tumors at low doses. In addition, matrix enzymes (such as hyaluronidase), matrix metalloproteinase (MMPs), especially matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9) have been modified in NPs to destroy the structure of ECM [180,181,182]. Ji’s team assembled the amphiphilic peptide of MMP-2 reaction and phospholipid to construct MMP-2 reactive peptide hybrid-liposome (MRPL) [182]. The pirfenidone (PFD) loaded MRPL can precisely release PFD at the site of the pancreatic tumor and down-regulate the various elements of the ECM by taking advantage of the MMP-2-rich pathological environment. As a result, gemcitabine is more able to penetrate and diffuse into tumor tissues, improving its ability to cure pancreatic cancers. Visibly, modification of NPs with related proteases that destroy ECM components can improve the diffusion of drug-loaded nanocarriers in tumors [173,178]. This is essential for the targeted delivery and release of anti-tumor drugs which may have better anti-tumor effects in combination with other strategies to improve the TME.

3.2. Nanocarriers for Activating Immunostimulatory Cells

Due to the complexity of the TME, the cloaking and mutation of tumor antigens lead to immune escape, resulting in immunostimulatory cells losing anti-tumor functions [83,166]. Previously, by using nanoparticles in combination with cancer vaccines, exogenous antigens, immunogenic cell death (ICD) inducers, and immune checkpoint regulators, antigen-presenting cells (antigen presenting cells (APCs), such as dendritic cells (DCs)) and T cell activity can be regulated to improve the local anti-tumor immunity of the TME (Figure 6). Therefore, activating immunostimulatory cells is the second effective strategy to reprogram the TME.
For activating DCs. Nanoparticles can deliver some tumor treatment drugs to tumor cells, causing the ICD effect of tumor cells, realizing tumor cells apoptosis, and transforming tumor cells into anti-tumor vaccines [183]. When ICD occurs in tumor cells, dead tumor cells calreticulin (CRT) will be exposed to the cell surface. At the same time, adenosine triphosphate (ATP) and high mobility group protein B1 (HMGB1) will be secreted and released. They will act on DCs and activate the antigen presentation function, thus activating the anti-tumor T cell response [163,184]. ICD-inducers include mitoxantrone and anthracyclines, oxaliplatin, UVC irradiation, radiotherapy, shikonin, bortezomib, cardiac glycosides (CGs), photodynamic therapy (PDT) with hypericin, and so on [185]. Recently, we prepared a biomimetic PLGA-based nanoparticle (NP) to co-encapsulate plumbagin and dihydrotanshinone (IPLB and DIH) [184]. This NP induced an ICD effect of liver cancer cells, activating DCs and T cells’ immune responses, and generating anti-liver cancer chemo-immunotherapeutic effects by remodeling the TME.
For activating T cells. Nanoparticles coated with PD-1/PD-L1-targeted ligands have become a new drug delivery system which can improve the drug delivery effect, enhance the immune response, and reduce the side effects of tumor treatment [186,187,188]. The nanoparticle-loading anti- PD-1/PD-L1 can effectively enhance the function of T cells. Consequently, the anti-tumor T cells immune response in TME will be activated. Zhang’s team reported that an engineered cell nano vesicle (NVs) presents PD-1 receptors on its membrane, breaking the PD-1/PD-L1 immunosuppressive axis and enhancing anti-tumor T cell immune responses [187]. In addition, indoleamine 2,3-dioxygenase inhibitors were loaded into PD-1 NVs, synergistically destroying the immune tolerance environment in TME. Importantly, PD-1 NVs significantly increase the infiltration of the CD8+ tumor, infiltrating lymphocytes (TILs) and directly driving the tumor killing response of CTL.
In conclusion, immunostimulatory cells such as DCs are one key step to activate an anti-tumor immune response; they can present tumor-associate antigen to CTL and secrete cytokines to activate CD4+ T or NKs. Therefore, activating immunostimulatory cells is important for enhancing the immune response of the TME.

3.3. Nanocarriers for Decreasing/Regulating Immunosuppressive Factors

The immunosuppressive tumor microenvironment is mainly composed of the complex interaction between immune-tolerance cells (e.g., M2-like TAMs, CAFs, MDSCs, Treg, etc.) and immunosuppressive factors (e.g., TGF-β, VEGF, IL-10,IL-4, HIF-α, etc.) with other cells or non-cells. Immune-tolerance cells and immunosuppressive molecules can promote tumor growth by promoting the formation of ECM and angiogenesis. The failure of immune cells (TAMs and Treg) also seriously affects the development of tumor treatment strategies. Therefore, nano therapies to overcome the immune tolerance of the TME is the third effective strategy to reprogram the TME (Figure 6).
For regulating immunosuppressive macrophages. Macrophages within the tumor, also known as TAMs, are a critical regulator of the immunosuppressive TME for immune escape and tumor development [189]. The majority of TAMs present M2 phenotype and produce immunosuppressive factors to support immunosuppressive cells [190,191]. In contrast to M2 TAMs, M1 generate immunostimulatory factors to activate immunostimulatory cells [192]. Thus, approaches used to polarize TAMs from M2 to M1 have demonstrated great potential for reprogramming the immunosuppressive TME. Chen’s team constructed a fibrin gel which encapsulated anti-CD47-loaded calcium carbonate nanoparticles [193]. This nanogel can scavenge H+ in the TME, reversing M2-like TAMs to the M1-like phenotype. The delivery anti-CD47 blocks the “don’t eat me” signal of cancer cells, causing macrophages to engulf more cancer cells. Macrophages can also act as professional APCs, delivering tumor-associated antigens to T cells to initiate the anti-tumor effect of CD4+ and CD8+ T cells. Shi’s team co-encapsulated photosensitizers indocyanine green (ICG) and titanium dioxide (TiO2) with or without ammonium bicarbonate (NH4HCO3) in mannose-modified PEGylated PLGA nanoparticles for the delivery of photosensitizers to endosome/lysosome or cytoplasm of TAMs [194]. They successfully reprogrammed M2-like TAMs to an anti-tumor M1-like phenotype using this NP, demonstrating superior efficiency and efficacy over lipopolysaccharide stimulation. Reprogrammed TAMs lead to changes in the tumor microenvironment, activation of their anti-tumor function, and release cytokines that recruit more CTLs in the tumor tissues and guide T cells to produce anti-tumor immune memory.
For regulating immunosuppressive MDSCs. The immunosuppression caused by MDSCs in TME involves many aspects, which can suppress the function of TAMs, T cells, and NK cells in the TME by producing immunosuppressive cytokines like VEGF, IL-10, and TGF-β [195]. MDSCs can also produce peroxynitrite (PNT) to alter the chemokines of TME to prevent the infiltration of T cells. The existence of MDSCs is one of the main reasons for the formation of immunosuppressive TME [46]. Therefore, it is a new strategy of targeting MDSCs to provide anti-tumor therapy. A targeted polymeric micellar nano delivery system (SUNb PM) was constructed. Multi target receptor tyrosine kinase inhibitors were encapsulated in it, cooperating with anti-cancer vaccine therapy to treat advanced melanoma [38]. SUNb PM not only increased the infiltration of CTLs and reduced the number of MDSCs and Treg in TME, but also increased the expression of Th1 type cytokines IL-2 and IFN-γ and downregulated the components related to fibroblasts, collagen, and blood vessels (e.g., CD31, α-SMA, and collagen).
For regulating immunosuppressive Treg cells. The CD4+ regulatory T (Treg) cells, as a wide range regulators of gene expression, are critical to the recognition and function of immune regulatory T cell subsets [196]. Tregs, through the activities of cell surface molecules (e.g., Foxp3, CTLA-4, CD25, CD39, CD73, and TIGIT), secretion of cytokines (TGF-β, CCR4), and immune molecules (granzyme, cyclic AMP, and IDO) create an immunosuppressive TME [46,197]. Therefore, blocking the expression of functional molecules on Treg or reducing the number of Treg can reshape immunosuppressed TME. Ou’s team developed tLyp1 peptide conjugated hybrid nanoparticles that target Treg cells of TME [198]. The hybrid nanoparticles presented good stability and effective targeting to Treg cells. By inhibiting the phosphorylation of STAT3 and STAT5, they enhance the downregulation of imatinib on Treg cells. Specifically, when combined with CTLA-4, the Treg cells were more reduced. Prolonged survival rate, inhibited tumor growth, and elevated CD8+ T cells infiltration were also observed.
For regulating immunosuppressive CAF and other immunosuppressive factors. Many other strategies have been conducted to reprogram the immunosuppressive TME through inhibiting angiogenesis, CAF function, and soluble immunosuppressive factors (TGF-β, CCL-2, and IL-6, VEGF). Cheng’s team reported a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor ECM for tumor-targeted delivery and on-demand release of a short D-peptide antagonist of programmed cell death-ligand 1 (D PPA-1) and an inhibitor of idoleamine 2, 3-dioxygenase (NLG919) [199]. By concurrent blockade of immune checkpoints and tryptophan metabolism, the nano-formulation increased the level of tumor-infiltrated cytotoxic T cells and, in turn, effectively inhibited melanoma growth. Hou’s team developed a nano lotion (NE) formula, targeting the delivery of anti-fibrosis drug fraxinellone (Frax) to CAFs as a method to reverse immunosuppressive TME of melanoma [200]. After intravenous injection of Frax NE, significant reductions of CAFs and interstitial deposition were observed. Immunostimulatory cells (NK cells, CTLs) and factors (IFN-γ, TNF-α) were also increased. Immunosuppress cells (regulatory B cells, MDSCs) and factors (TGF-β, CCL-2, and IL-6) were also decreased in the TME. Cecchini’s team reported successful production of molecularly imprinted polymer nanoparticles (nanoMIPs) against human vascular endothelial growth factor (VEGF) [201]. The composite nanoparticles exhibited specific homing towards human melanoma cell xenografts, overexpressing hVEGF in zebrafish embryos. This nanoMIP can deliver anti-angiogenic drugs that inhibit the development of tumors.
In conclusion, the TME is a determining factor of the anticancer response and can endow resistance to various anti-tumor therapies. In this context, nanomaterials have been shown to alter populations of CAFs, TAMs, regulatory T cells, and MDSCs. Although considerable progress has been made, in order to translate this strategy into clinical trials, nanomaterial based TME modulation must overcome several limitations, including limited tumor tissue penetration, tumor heterogeneity, and immunotoxicity. Combined treatment with traditional treatment, such as surgery, chemotherapy, photodynamic, etc., may be an effective strategy to solve these problems.

3.4. Nanocarriers for Regulating Acidic Environment

The acidic environment in the tumor microenvironment has become a hot topic in cancer biology research. Many studies have shown that tumor tissues generally have a lower pH value compared to normal tissues [166]. This acidic environment may play a crucial role in tumor growth and metastasis.
The metabolic processes of tumor cells can lead to the formation of an acidic environment. For example, tumor cells often have a high rate of glycolysis, producing a large amount of lactic acid and thus reducing the pH value of the surrounding tissue. In addition, the high metabolic rate of tumor cells also leads to increased carbonic anhydrase activity, which accelerates the reaction between carbon dioxide and water to generate a large amount of acidic metabolites [202].
The acidic environment can promote tumor cell proliferation and invasion. On the one hand, a low pH value can promote the inhibition of cell apoptosis, thus, increasing cell survival rate. On the other hand, the acidic environment can also promote tumor cell migration and invasion, as the low pH value increases the protease activity on the cell surface, promoting the interaction between cells and the extracellular matrix.
However, the acidic environment can also have a negative impact on tumor treatment. Some studies have shown that a low pH value can weaken the effectiveness of treatment methods such as radiotherapy and chemotherapy [203]. This is because the low pH value reduces the effective concentration of drugs within the cell, thus decreasing the effectiveness of treatment.
Therefore, exploring the effects of the acidic environment in the tumor microenvironment on tumor growth and treatment has become a hot topic in the field of cancer research. By delving deeper into the metabolic processes of tumor cells and the mechanisms underlying the formation of the acidic environment, it is hoped that more effective tumor treatment strategies can be developed, thus improving the effectiveness and prognosis of cancer treatment.
Nanocarriers can improve the acidic environment of tumor sites in multiple ways. One method is to use nanomaterials with acidic degradation properties. In this way, drugs can be released at the tumor site and gradually degrade over time, reducing local acidity. Siriwallee et al. constructed a type of aminohepthamine cyanine based thermal probe (I2-IR783-Mpip) to achieve photodynamic therapy with specific response to acidic environment at tumor site [204]. Jingyi An et al. used OVA as a template to mineralize calcium carbonate and used the acid degradation reaction of calcium carbonate to improve the pH of tumor sites to enhance the effect of immunotherapy [165]. Som et al. believe that it is impractical and non-selective to use alkaline fluid or proton pump inhibitor to improve the acidic environment of tumors. Therefore, they prepared a series of calcium carbonate nanoparticles with different particle sizes to achieve the function of regulating the acidity of tumor sites [205].
Although nano-carriers have the potential to improve the acidic environment of tumor sites, there are still many technical and safety challenges in their application. In the future, further research and development are needed to give full play to the potential of nano-carriers in tumor treatment.

3.5. Nanocarriers for Regulating Hypoxia and Redox Environment

The oxidative–reductive environment at the tumor site refers to the oxidative–reductive state of cells within the tumor tissue; this is an important difference between tumor cells and normal cells. In the tumor site, the cell metabolism rate is higher than that in normal tissue, resulting in high metabolic activity and cell proliferation. At the same time, the blood supply and vascular generation capacity in tumor tissue are relatively low, leading to low oxygen tension and the formation of a hypoxic state [206]. Therefore, improving the hypoxia condition at the tumor site can effectively inhibit tumor proliferation and improve the treatment effect of chemotherapy, photothermal therapy, and other means. High biocompatibility and oxygen solubility make hemoglobin (Hb) and perfluorocarbon (PFC) effective oxygen transporters [207,208]. Tian et al. used hemoglobin nanoparticles coated by cancer cell membrane to improve the hypoxic environment of tumor sites and significantly enhance the chemotherapy effect of doxorubicin [209]. Song et al. constructed a PEG-modified nanoparticle with tantalum oxide (TaOx) as the core and PFC as the shell [210]. By taking advantage of the high oxygen load of PFC and the X-ray absorption characteristics of TaOx, the improvement of the hypoxia environment at the tumor site and the radiosensitivity of tumor treatment were achieved.
Hypoxia also results in a difference in the oxidative–reductive environment within the tumor tissue compared to normal tissue. In tumor tissue, there are usually higher levels of oxygen and nitrogen free radicals, which can trigger oxidative stress reactions [211]. These free radicals affect biological macromolecules such as proteins, lipids, and DNA through oxidation–reduction reactions, leading to cell damage and death. In addition, tumor cells typically exhibit higher concentrations of glutathione (GSH), the main reducing ligand of a tumor site. The highest concentration of GSH is found in the cytoplasm of tumors (2–10 mmol·L−1), which is substantially higher than its extracellular concentration (2–20 μmol·L−1). The GSH concentration in tumor tissue is at least four times higher than that in normal tissue.
The oxidative–reductive environment at the tumor site is of significant importance for the development and treatment of tumors. The proliferation and escape of tumor cells are often influenced by the oxidative–reductive environment. By regulating the oxidative–reductive balance within tumor cells, tumor growth and metastasis can be inhibited. Shuang Bai et al. prepared a star-liked polymer, β- CD-b-P (CPTGSH-co-CPTROS-co-OEGMA) (CPGR), that can respond to both the high ROS environment and the high GSH environment at the tumor site. This polymer can realize the synergistic effect of chemotherapy [211]. Weikai Chen et al. have prepared an alginate gel that can use calcium ions at the tumor site to self-crosslink. The gel includes protoporphyrin (PpIX) modified manese oxide (MnO2) nanoparticles and buthionine-sulfoximine (BSO), where MnO2, as a catalyst, can produce oxygen, while BSO inhibits GSH synthesis of cells, so as to improve the tumor microenvironment. Xin Guan et al. prepared a flaky inorganic nanoparticle Nb2C, which carried TiO2 and l-buthionine-sulfoximine to inhibit the synthesis of GSH in tumor cells, affecting the microenvironment of the tumor [212].
Tumor cells need a large amount of oxygen and nutrients when they grow and divide, but their blood supply is usually insufficient, resulting in hypoxia in tumor tissue accompanied by an abnormal redox environment. Hypoxia and abnormal redox environment in tumor site will increase the viability of tumor cells and limit the effect of traditional radiotherapy and chemotherapy. Now, more and more advanced nanotechnology has provided some innovative solutions to the problems of hypoxia and abnormal redox environment at tumor sites. The tumor treatment scheme based on the above nanotechnology has broad clinical prospects.

4. Conclusions and Outlook

Over the last few years, cancer targeting therapy based on nanotechnology has gained tremendous attention. Cancer immunotherapy is especially expected to be a game changer for modern cancer therapy. Cancer immunotherapy has made the biggest breakthroughs in recent years, including therapies such as immunotherapy with CAR-T and PD-1/PD-L1 antibodies [9,32,188,213]. However, the patient response rates to such creative treatments remain modest, resulting in several preclinical studies and clinical trials that have directed more attention toward the immunosuppressive TME [9,186,214].
Abundant immunosuppressive mechanisms in tumors make it difficult to achieve effective therapeutic effect by single therapy. The controlled release and multi-directional carrier properties of targeted nano-platforms can comprehensively inhibit multiple immune pathways, making cancer immunotherapy more effective. Nanomaterial-based modulation of the TME has been studied for its potential to enhance the efficacy of cancer therapy. Nanomaterials that disrupt the ECM and/or tumor vasculature and increase blood perfusion have been developed to increase the penetration and intracellular delivery of anticancer agents. Nanomaterials that modulate DCs, CAFs, TAMs, Treg cells, or MDSCs have been shown to alter the activities and populations of immune cells in the TME. However, the immune-related adverse events from enhanced immune strategy occur frequently. In order to promote the success of clinical transformation, it is necessary to comprehensively evaluate the safety and immune side effects of nanotechnology.
In addition, nanocarriers interact with different molecules, cells, tissues, and organs as they are transported through the body. Consequently, biological barriers in the body trap most of these nanoparticles, making it extremely rare for them to reach the tumor site [215]. In order to obtain multifunctional drug delivery nanomaterials with stable groups, targeted ligands, and bio-responsive linkers, complex modifications are required. However, this may increase the obstacles to large-scale, causing repeatable production of nanomaterials and unexpected side effects. Therefore, further investigation must be performed to maintain the balance between the therapeutic benefit, the complexity of formulation preparation/scale-up, and the risk of toxicity before nano-immunotherapy can be satisfactorily applied for cancer patients.
The rational combination of various cancer targeting treatments based on nanotechnology will result in more efficient cancer inhibition and elimination. A combined therapy strategy can inhibit the occurrence and development of tumor from multiple methods and improve the efficiency of eliminating tumors. Therefore, during the design of a nanomaterial, the combination of multiple treatment methods should be considered. In addition, the powerful advantage of ‘mimicking nature’ still overcomes many of the disadvantages of traditional delivery nanoparticles and provides a more effective strategy for cancer treatment. The natural characteristics of cells, such as the enrichment of targeted proteins, long-term circulation in the body, ability to pass through biological barriers, interactions with other cells, and reduced tissue and cell toxicity, effectively protect the drug delivery of nanoparticles and substantially improve the therapeutic effect. With the rapid development of material science, nanotechnology, pharmacology, bioinformatics, and proteomics, biomimetic nanomaterials are expected to change the current medical technology, overcome many obstacles, and provide new horizons for targeted cancer combination therapy.
According to the research papers on nano-carriers and tumor therapy collected as widely as possible in the past 10 years from 2011 to 2022, although the nano-carriers developed so far have played an excellent role in tumor targeted therapy and tumor microenvironment improvement, the application of nano-carriers still faces limitations of biosafety and clinical technology. To fully exploit the potential of nano-carriers in the treatment of tumors, additional research and development will be required in the future.

Author Contributions

Conceptualization, S.H.; data curation, S.H.; writing—original draft preparation, S.H.; writing—review and editing, Y.C. and Z.Y.; visualization, Y.C.; supervision, L.W.; project administration, J.M.; funding acquisition, L.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (Grant number 81973262, 82011530138, 81970660) and Beijing Natural Science Foundation (Grant No. L202039).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

The list of abbreviations
AbbreviationFull Spelling
TMEtumor microenvironment
TAMtumor associated macrophage
NPsnanoparticles
PD-1programmed cell death protein 1
CTLA-4cytotoxic T lymphocyte-associated protein 4
CAR-Tchimeric antigen receptors T cells
DCsdendritic cells
ThT helper (Th) cells
CTLscytotoxic T lymphocytes
NKnatural killer cells
MDSCsmyeloid-derived suppressor cells
Tregregulatory T cells
CAFscancer-associated fibroblasts
ECMextracellular matrix
FDAUS Food and Drug Administration
BSAbovine serum albumin
ICGindocyanine green
MSNPsmesoporous silica nanoparticles
DOXdoxorubicin
FAfolate
LPsliposomes
MT1DPmetallothionein 1D
ROSreactive oxygen species
OMlipsmodified magnetic liposomes
OAoleanolic acid
EPRenhance permeability and retention
HCCPhexachlorocyclic-triphosphonitrile
CysMcysteine derivatives
IDOindoleamine-(2,3)-dioxygenase
cRGDcyclo (Arg-Gly-Asp-D-Tyr-Lys) peptide
TRPl-tryptophan
KYNL-kynurenine
SPIONSsupermagnetic iron oxide NPs
TZBtrastuzumab
PLGApoly(lactic-co-glycolic acid
Magmagnolol
HER2human epidermal growth factor-2
NOPDNO photodonor
RBCred blood cell
CCMcancer cell membrane
EVsextracellular vehicles
GBManti-glioblastoma
ESCsembryonic stem cells
PTXpaclitaxel
ECMextracellular matrix
rHuPH20recombinant human hyaluronidase PH20
HAhyaluronidase
MMPsmatrix metalloproteinase
MRPLMMP-2 reactive peptide hybrid-liposome
PFDpirfenidone
APCsantigen presenting cells
ICDimmunogenic cell death
CRTdead tumor cells calreticulin
ATPadenosine triphosphate
HMGB1high mobility group protein B1
CGscardiac glycosides
PDTPhotodynamic therapy
IPLBplumbagin
DIHdihydrotanshinone
NVsnano vesicle
TILstumor infiltrating lymphocytes
PNTperoxynitrite
SUNb PMpolymeric micellar nano delivery system
DPPA-1programmed cell death-ligand 1
NLG91idoleamine 2, 3-dioxygenase
NEnano lotion
Fraxfraxinellone
VEGFhuman vascular endothelial growth factor
Hbhemoglobin
PFCperfluorocarbon
GSHglutathione
CPGRβ- CD-b-P (CPTGSH-co-CPTROS-co-OEGMA)
PpIXprotoporphyrin
BSObuthionine-sulfoximine

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  2. Goldman, A.; Kulkarni, A.; Kohandel, M.; Pandey, P.; Rao, P.; Natarajan, S.K.; Sabbisetti, V.; Sengupta, S. Rationally Designed 2-in-1 Nanoparticles Can Overcome Adaptive Resistance in Cancer. ACS Nano 2016, 10, 5823–5834. [Google Scholar] [CrossRef]
  3. Wu, X.; Wu, Y.; Ye, H.; Yu, S.; He, C.; Chen, X. Interleukin-15 and cisplatin co-encapsulated thermosensitive polypeptide hydrogels for combined immuno-chemotherapy. J. Control. Release 2017, 255, 81–93. [Google Scholar] [CrossRef] [PubMed]
  4. Treat, L.H.; McDannold, N.; Zhang, Y.; Vykhodtseva, N.; Hynynen, K. Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma. Ultrasound Med. Biol. 2012, 38, 1716–1725. [Google Scholar] [CrossRef] [Green Version]
  5. Coffey, J.C.; Wang, J.H.; Smith, M.J.; Bouchier-Hayes, D.; Cotter, T.G.; Redmond, H.P. Excisional surgery for cancer cure: Therapy at a cost. Lancet Oncol. 2003, 4, 760–768. [Google Scholar] [CrossRef] [PubMed]
  6. Li, F.; Zhang, T.; Cao, L.; Zhang, Y. Chimeric Antigen Receptor T Cell Based Immunotherapy for Cancer. Curr. Stem Cell Res. Ther. 2018, 13, 327–335. [Google Scholar] [CrossRef]
  7. Kennedy, L.B.; Salama, A.K.S. A review of cancer immunotherapy toxicity. CA Cancer J. Clin. 2020, 70, 86–104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Marshall, H.T.; Djamgoz, M.B.A. Immuno-Oncology: Emerging Targets and Combination Therapies. Front. Oncol. 2018, 8, 315. [Google Scholar] [CrossRef]
  9. Rodriguez-Garcia, A.; Lynn, R.C.; Poussin, M.; Eiva, M.A.; Shaw, L.C.; O’Connor, R.S.; Minutolo, N.G.; Casado-Medrano, V.; Lopez, G.; Matsuyama, T.; et al. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy. Nat. Commun. 2021, 12, 877. [Google Scholar] [CrossRef]
  10. Yang, Y.; Guo, J.; Huang, L. Tackling TAMs for Cancer Immunotherapy: It’s Nano Time. Trends Pharmacol. Sci. 2020, 41, 701–714. [Google Scholar] [CrossRef]
  11. Wu, D.; Wang, S.; Yu, G.; Chen, X. Cell Death Mediated by the Pyroptosis Pathway with the Aid of Nanotechnology: Prospects for Cancer Therapy. Angew. Chem. Int. Ed. Engl. 2021, 60, 8018–8034. [Google Scholar] [CrossRef]
  12. Le, Q.V.; Suh, J.; Oh, Y.K. Nanomaterial-Based Modulation of Tumor Microenvironments for Enhancing Chemo/Immunotherapy. AAPS J. 2019, 21, 64. [Google Scholar] [CrossRef]
  13. Gajewski, T.F.; Schreiber, H.; Fu, Y.X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 2013, 14, 1014–1022. [Google Scholar] [CrossRef] [Green Version]
  14. Han, S.; Wang, W.; Wang, S.; Yang, T.; Zhang, G.; Wang, D.; Ju, R.; Lu, Y.; Wang, H.; Wang, L. Tumor microenvironment remodeling and tumor therapy based on M2-like tumor associated macrophage-targeting nano-complexes. Theranostics 2021, 11, 2892–2916. [Google Scholar] [CrossRef]
  15. Ho, T.T.B.; Nasti, A.; Seki, A.; Komura, T.; Inui, H.; Kozaka, T.; Kitamura, Y.; Shiba, K.; Yamashita, T.; Yamashita, T.; et al. Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis. J. Immunother. Cancer 2020, 8, e001367. [Google Scholar] [CrossRef] [PubMed]
  16. Jin, F.; Liu, D.; Xu, X.; Ji, J.; Du, Y. Nanomaterials-Based Photodynamic Therapy with Combined Treatment Improves Antitumor Efficacy Through Boosting Immunogenic Cell Death. Int. J. Nanomed. 2021, 16, 4693–4712. [Google Scholar] [CrossRef] [PubMed]
  17. Liu, Q.; Chen, X.; Jia, J.; Zhang, W.; Yang, T.; Wang, L.; Ma, G. pH-Responsive Poly(D,L-lactic-co-glycolic acid) Nanoparticles with Rapid Antigen Release Behavior Promote Immune Response. ACS Nano 2015, 9, 4925–4938. [Google Scholar] [CrossRef]
  18. Lv, W.; Cao, M.; Liu, J.; Hei, Y.; Bai, J. Tumor microenvironment-responsive nanozymes achieve photothermal-enhanced multiple catalysis against tumor hypoxia. Acta Biomater. 2021, 135, 617–627. [Google Scholar] [CrossRef]
  19. Zhu, L.J.; Gu, L.S.; Shi, T.Y.; Zhang, X.Y.; Sun, B.W. Enhanced treatment effect of nanoparticles containing cisplatin and a GSH-reactive probe compound. Mater. Sci. Eng. C Mater. Biol. Appl. 2019, 96, 635–641. [Google Scholar] [CrossRef] [PubMed]
  20. Du, X.; Yang, X.; Zhang, Y.; Gao, S.; Liu, S.; Ji, J.; Zhai, G. Transdermal delivery system based on heparin-modified graphene oxide for deep transportation, tumor microenvironment regulation, and immune activation. Nano Today 2022, 46, 101565. [Google Scholar] [CrossRef]
  21. Liu, Y.; Qiao, L.; Zhang, S.; Wan, G.; Chen, B.; Zhou, P.; Zhang, N.; Wang, Y. Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy. Acta Biomater. 2018, 66, 310–324. [Google Scholar] [CrossRef]
  22. Lu, J.; Liu, X.; Liao, Y.P.; Wang, X.; Ahmed, A.; Jiang, W.; Ji, Y.; Meng, H.; Nel, A.E. Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway. ACS Nano 2018, 12, 11041–11061. [Google Scholar] [CrossRef] [Green Version]
  23. Feng, X.; Li, F.; Zhang, L.; Liu, W.; Wang, X.; Zhu, R.; Qiao, Z.A.; Yu, B.; Yu, X. TRAIL-modified, doxorubicin-embedded periodic mesoporous organosilica nanoparticles for targeted drug delivery and efficient antitumor immunotherapy. Acta Biomater. 2022, 143, 392–405. [Google Scholar] [CrossRef]
  24. Khranovska, N.; Skachkova, O.; Gorbach, O.; Inomistova, M.; Orel, V. Magnetically sensitive nanocomplex enhances antitumor efficacy of dendritic cell-based immunotherapy. Exp. Oncol. 2021, 43, 217–223. [Google Scholar] [CrossRef] [PubMed]
  25. Han, S.; Wang, W.; Wang, S.; Wang, S.; Ju, R.; Pan, Z.; Yang, T.; Zhang, G.; Wang, H.; Wang, L. Multifunctional biomimetic nanoparticles loading baicalin for polarizing tumor-associated macrophages. Nanoscale 2019, 11, 20206–20220. [Google Scholar] [CrossRef]
  26. Mulla, M.Z.; Rahman, M.R.T.; Marcos, B.; Tiwari, B.; Pathania, S. Poly Lactic Acid (PLA) Nanocomposites: Effect of Inorganic Nanoparticles Reinforcement on Its Performance and Food Packaging Applications. Molecules 2021, 26, 1967. [Google Scholar] [CrossRef]
  27. Skoberne, M.; Yewdall, A.; Bahjat, K.S.; Godefroy, E.; Lauer, P.; Lemmens, E.; Liu, W.; Luckett, W.; Leong, M.; Dubensky, T.W.; et al. KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of antitumor immunity. J. Clin. Investig. 2008, 118, 3990–4001. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Bonehill, A.; Van Nuffel, A.M.; Corthals, J.; Tuyaerts, S.; Heirman, C.; François, V.; Colau, D.; van der Bruggen, P.; Neyns, B.; Thielemans, K. Single-step antigen loading and activation of dendritic cells by mRNA electroporation for the purpose of therapeutic vaccination in melanoma patients. Clin. Cancer Res. 2009, 15, 3366–3375. [Google Scholar] [CrossRef] [Green Version]
  29. Kranz, L.M.; Diken, M.; Haas, H.; Kreiter, S.; Loquai, C.; Reuter, K.C.; Meng, M.; Fritz, D.; Vascotto, F.; Hefesha, H.; et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 2016, 534, 396–401. [Google Scholar] [CrossRef] [PubMed]
  30. De Vries, J.; Figdor, C. Immunotherapy: Cancer vaccine triggers antiviral-type defences. Nature 2016, 534, 329–331. [Google Scholar] [CrossRef]
  31. Wang, S.; Guo, J.; Bai, Y.; Sun, C.; Wu, Y.; Liu, Z.; Liu, X.; Wang, Y.; Wang, Z.; Zhang, Y.; et al. Bacterial outer membrane vesicles as a candidate tumor vaccine platform. Front. Immunol. 2022, 13, 987419. [Google Scholar] [CrossRef]
  32. Ye, B.; Hu, Y.; Zhang, M.; Huang, H. Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang Da Xue Xue Bao Yi Xue Ban 2022, 51, 185–191. [Google Scholar] [CrossRef] [PubMed]
  33. Wang, X.; Liu, Y.; Xue, C.; Hu, Y.; Zhao, Y.; Cai, K.; Li, M.; Luo, Z. A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses. Nat. Commun. 2022, 13, 5685. [Google Scholar] [CrossRef]
  34. Wang, C.; Ye, Y.; Hochu, G.M.; Sadeghifar, H.; Gu, Z. Enhanced Cancer Immunotherapy by Microneedle Patch-Assisted Delivery of Anti-PD1 Antibody. Nano Lett. 2016, 16, 2334–2340. [Google Scholar] [CrossRef]
  35. Zhang, N.; Song, J.; Liu, Y.; Liu, M.; Zhang, L.; Sheng, D.; Deng, L.; Yi, H.; Wu, M.; Zheng, Y.; et al. Photothermal therapy mediated by phase-transformation nanoparticles facilitates delivery of anti-PD1 antibody and synergizes with antitumor immunotherapy for melanoma. J. Control. Release 2019, 306, 15–28. [Google Scholar] [CrossRef] [PubMed]
  36. Xu, Z.; Ramishetti, S.; Tseng, Y.C.; Guo, S.; Wang, Y.; Huang, L. Multifunctional nanoparticles co-delivering Trp2 peptide and CpG adjuvant induce potent cytotoxic T-lymphocyte response against melanoma and its lung metastasis. J. Control. Release 2013, 172, 259–265. [Google Scholar] [CrossRef] [PubMed]
  37. Zhao, Y.; Huo, M.; Xu, Z.; Wang, Y.; Huang, L. Nanoparticle delivery of CDDO-Me remodels the tumor microenvironment and enhances vaccine therapy for melanoma. Biomaterials 2015, 68, 54–66. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Huo, M.; Zhao, Y.; Satterlee, A.B.; Wang, Y.; Xu, Y.; Huang, L. Tumor-targeted delivery of sunitinib base enhances vaccine therapy for advanced melanoma by remodeling the tumor microenvironment. J. Control. Release 2017, 245, 81–94. [Google Scholar] [CrossRef] [Green Version]
  39. Sasso, M.S.; Lollo, G.; Pitorre, M.; Solito, S.; Pinton, L.; Valpione, S.; Bastiat, G.; Mandruzzato, S.; Bronte, V.; Marigo, I.; et al. Low dose gemcitabine-loaded lipid nanocapsules target monocytic myeloid-derived suppressor cells and potentiate cancer immunotherapy. Biomaterials 2016, 96, 47–62. [Google Scholar] [CrossRef]
  40. Zhan, X.; Jia, L.; Niu, Y.; Qi, H.; Chen, X.; Zhang, Q.; Zhang, J.; Wang, Y.; Dong, L.; Wang, C. Targeted depletion of tumour-associated macrophages by an alendronate-glucomannan conjugate for cancer immunotherapy. Biomaterials 2014, 35, 10046–10057. [Google Scholar] [CrossRef]
  41. Wang, L.; Niu, M.; Zheng, C.; Zhao, H.; Niu, X.; Li, L.; Hu, Y.; Zhang, Y.; Shi, J.; Zhang, Z. A Core-Shell Nanoplatform for Synergistic Enhanced Sonodynamic Therapy of Hypoxic Tumor via Cascaded Strategy. Adv. Healthc. Mater. 2018, 7, e1800819. [Google Scholar] [CrossRef]
  42. Qin, L.; Gao, H. The application of nitric oxide delivery in nanoparticle-based tumor targeting drug delivery and treatment. Asian J. Pharm. Sci. 2019, 14, 380–390. [Google Scholar] [CrossRef]
  43. Cao, J.; Zheng, M.; Sun, Z.; Li, Z.; Qi, X.; Shen, S. One-Step Fabrication of Multifunctional PLGA-HMME-DTX@MnO(2) Nanoparticles for Enhanced Chemo-Sonodynamic Antitumor Treatment. Int. J. Nanomed. 2022, 17, 2577–2591. [Google Scholar] [CrossRef] [PubMed]
  44. Chen, S.X.; Zhang, J.; Xue, F.; Liu, W.; Kuang, Y.; Gu, B.; Song, S.; Chen, H. In situ forming oxygen/ROS-responsive niche-like hydrogel enabling gelation-triggered chemotherapy and inhibition of metastasis. Bioact. Mater. 2023, 21, 86–96. [Google Scholar] [CrossRef] [PubMed]
  45. Huang, J.; Liu, F.; Han, X.; Zhang, L.; Hu, Z.; Jiang, Q.; Wang, Z.; Ran, H.; Wang, D.; Li, P. Nanosonosensitizers for Highly Efficient Sonodynamic Cancer Theranostics. Theranostics 2018, 8, 6178–6194. [Google Scholar] [CrossRef] [PubMed]
  46. Sun, Y.; Ma, W.; Yang, Y.; He, M.; Li, A.; Bai, L.; Yu, B.; Yu, Z. Cancer nanotechnology: Enhancing tumor cell response to chemotherapy for hepatocellular carcinoma therapy. Asian J. Pharm. Sci. 2019, 14, 581–594. [Google Scholar] [CrossRef] [PubMed]
  47. Yang, G.; Ji, J.; Liu, Z. Multifunctional MnO(2) nanoparticles for tumor microenvironment modulation and cancer therapy. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2021, 13, e1720. [Google Scholar] [CrossRef]
  48. Srivatsan, A.; Jenkins, S.V.; Jeon, M.; Wu, Z.; Kim, C.; Chen, J.; Pandey, R.K. Gold nanocage-photosensitizer conjugates for dual-modal image-guided enhanced photodynamic therapy. Theranostics 2014, 4, 163–174. [Google Scholar] [CrossRef]
  49. Hu, Y.; Yang, Y.; Wang, H.; Du, H. Synergistic Integration of Layer-by-Layer Assembly of Photosensitizer and Gold Nanorings for Enhanced Photodynamic Therapy in the Near Infrared. ACS Nano 2015, 9, 8744–8754. [Google Scholar] [CrossRef]
  50. Kumthekar, P.; Ko, C.H.; Paunesku, T.; Dixit, K.; Sonabend, A.M.; Bloch, O.; Tate, M.; Schwartz, M.; Zuckerman, L.; Lezon, R.; et al. A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma. Sci. Transl. Med. 2021, 13, eabb3945. [Google Scholar] [CrossRef]
  51. Haque, S.; Norbert, C.C.; Acharyya, R.; Mukherjee, S.; Kathirvel, M.; Patra, C.R. Biosynthesized Silver Nanoparticles for Cancer Therapy and In Vivo Bioimaging. Cancers 2021, 13, 6114. [Google Scholar] [CrossRef]
  52. He, Y.; Du, Z.; Ma, S.; Liu, Y.; Li, D.; Huang, H.; Jiang, S.; Cheng, S.; Wu, W.; Zhang, K.; et al. Effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo. Int. J. Nanomed. 2016, 11, 1879–1887. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Ma, X.; Qu, Q.; Zhao, Y. Targeted delivery of 5-aminolevulinic acid by multifunctional hollow mesoporous silica nanoparticles for photodynamic skin cancer therapy. ACS Appl. Mater. Interfaces 2015, 7, 10671–10676. [Google Scholar] [CrossRef]
  54. Tu, J.; Wang, T.; Shi, W.; Wu, G.; Tian, X.; Wang, Y.; Ge, D.; Ren, L. Multifunctional ZnPc-loaded mesoporous silica nanoparticles for enhancement of photodynamic therapy efficacy by endolysosomal escape. Biomaterials 2012, 33, 7903–7914. [Google Scholar] [CrossRef]
  55. Mrozek, E.; Rhoades, C.A.; Allen, J.; Hade, E.M.; Shapiro, C.L. Phase I trial of liposomal encapsulated doxorubicin (Myocet; D-99) and weekly docetaxel in advanced breast cancer patients. Ann. Oncol. 2005, 16, 1087–1093. [Google Scholar] [CrossRef] [PubMed]
  56. Gibbs, D.D.; Pyle, L.; Allen, M.; Vaughan, M.; Webb, A.; Johnston, S.R.; Gore, M.E. A phase I dose-finding study of a combination of pegylated liposomal doxorubicin (Doxil), carboplatin and paclitaxel in ovarian cancer. Br. J. Cancer 2002, 86, 1379–1384. [Google Scholar] [CrossRef] [Green Version]
  57. James, N.D.; Coker, R.J.; Tomlinson, D.; Harris, J.R.; Gompels, M.; Pinching, A.J.; Stewart, J.S. Liposomal doxorubicin (Doxil): An effective new treatment for Kaposi’s sarcoma in AIDS. Clin. Oncol. R. Coll. Radiol. 1994, 6, 294–296. [Google Scholar] [CrossRef]
  58. Li, G.; Liu, D.; Kimchi, E.T.; Kaifi, J.T.; Qi, X.; Manjunath, Y.; Liu, X.; Deering, T.; Avella, D.M.; Fox, T.; et al. Nanoliposome C6-Ceramide Increases the Anti-tumor Immune Response and Slows Growth of Liver Tumors in Mice. Gastroenterology 2018, 154, 1024–1036.e9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Vasey, P.A.; Kaye, S.B.; Morrison, R.; Twelves, C.; Wilson, P.; Duncan, R.; Thomson, A.H.; Murray, L.S.; Hilditch, T.E.; Murray, T.; et al. Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin]: First member of a new class of chemotherapeutic agents-drug-polymer conjugates. Cancer Research Campaign Phase I/II Committee. Clin. Cancer Res. 1999, 5, 83–94. [Google Scholar]
  60. Park, K.; Lee, S.; Kang, E.; Kim, K.; Choi, K.; Kwon, I.C. New Generation of Multifunctional Nanoparticles for Cancer Imaging and Therapy. Adv. Funct. Mater. 2009, 19, 1553–1566. [Google Scholar] [CrossRef]
  61. Kim, T.Y.; Kim, D.W.; Chung, J.Y.; Shin, S.G.; Kim, S.C.; Heo, D.S.; Kim, N.K.; Bang, Y.J. Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin. Cancer Res. 2004, 10, 3708–3716. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Zamboni, W.C. Liposomal, nanoparticle, and conjugated formulations of anticancer agents. Clin. Cancer Res. 2005, 11, 8230–8234. [Google Scholar] [CrossRef] [Green Version]
  63. Xiong, S.; Yu, B.; Wu, J.; Li, H.; Lee, R.J. Preparation, therapeutic efficacy and intratumoral localization of targeted daunorubicin liposomes conjugating folate-PEG-CHEMS. Biomed. Pharmacother. 2011, 65, 2–8. [Google Scholar] [CrossRef] [PubMed]
  64. Wang, H.X.; Xiong, M.H.; Wang, Y.C.; Zhu, J.; Wang, J. N-acetylgalactosamine functionalized mixed micellar nanoparticles for targeted delivery of siRNA to liver. J. Control. Release 2013, 166, 106–114. [Google Scholar] [CrossRef] [PubMed]
  65. Teo, J.Y.; Chin, W.; Ke, X.; Gao, S.; Liu, S.; Cheng, W.; Hedrick, J.L.; Yang, Y.Y. pH and redox dual-responsive biodegradable polymeric micelles with high drug loading for effective anticancer drug delivery. Nanomedicine 2017, 13, 431–442. [Google Scholar] [CrossRef] [PubMed]
  66. Uchida, H.; Itaka, K.; Nomoto, T.; Ishii, T.; Suma, T.; Ikegami, M.; Miyata, K.; Oba, M.; Nishiyama, N.; Kataoka, K. Modulated protonation of side chain aminoethylene repeats in N-substituted polyaspartamides promotes mRNA transfection. J. Am. Chem. Soc. 2014, 136, 12396–12405. [Google Scholar] [CrossRef] [Green Version]
  67. Bobo, D.; Robinson, K.J.; Islam, J.; Thurecht, K.J.; Corrie, S.R. Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date. Pharm. Res. 2016, 33, 2373–2387. [Google Scholar] [CrossRef]
  68. Verschraegen, C.F.; Skubitz, K.; Daud, A.; Kudelka, A.P.; Rabinowitz, I.; Allievi, C.; Eisenfeld, A.; Singer, J.W.; Oldham, F.B. A phase I and pharmacokinetic study of paclitaxel poliglumex and cisplatin in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 2009, 63, 903–910. [Google Scholar] [CrossRef]
  69. Caster, J.M.; Patel, A.N.; Zhang, T.; Wang, A. Investigational nanomedicines in 2016: A review of nanotherapeutics currently undergoing clinical trials. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2017, 9, e1416. [Google Scholar] [CrossRef]
  70. Ventola, C.L. Progress in Nanomedicine: Approved and Investigational Nanodrugs. Pharm. Ther. 2017, 42, 742–755. [Google Scholar]
  71. Akbarzadeh, A.; Samiei, M.; Joo, S.W.; Anzaby, M.; Hanifehpour, Y.; Nasrabadi, H.T.; Davaran, S. Synthesis, characterization and in vitro studies of doxorubicin-loaded magnetic nanoparticles grafted to smart copolymers on A549 lung cancer cell line. J. Nanobiotechnol. 2012, 10, 46. [Google Scholar] [CrossRef] [Green Version]
  72. Oroojalian, F.; Beygi, M.; Baradaran, B.; Mokhtarzadeh, A.; Shahbazi, M.A. Immune Cell Membrane-Coated Biomimetic Nanoparticles for Targeted Cancer Therapy. Small 2021, 17, e2006484. [Google Scholar] [CrossRef] [PubMed]
  73. Bol, K.F.; Schreibelt, G.; Gerritsen, W.R.; de Vries, I.J.; Figdor, C.G. Dendritic Cell-Based Immunotherapy: State of the Art and Beyond. Clin. Cancer Res. 2016, 22, 1897–1906. [Google Scholar] [CrossRef] [Green Version]
  74. Cao, X.; Hu, Y.; Luo, S.; Wang, Y.; Gong, T.; Sun, X.; Fu, Y.; Zhang, Z. Neutrophil-mimicking therapeutic nanoparticles for targeted chemotherapy of pancreatic carcinoma. Acta Pharm. Sin. B 2019, 9, 575–589. [Google Scholar] [CrossRef] [PubMed]
  75. Chu, D.; Zhao, Q.; Yu, J.; Zhang, F.; Zhang, H.; Wang, Z. Nanoparticle Targeting of Neutrophils for Improved Cancer Immunotherapy. Adv. Healthc. Mater. 2016, 5, 1088–1093. [Google Scholar] [CrossRef] [Green Version]
  76. Choi, B.; Park, W.; Park, S.B.; Rhim, W.K.; Han, D.K. Recent trends in cell membrane-cloaked nanoparticles for therapeutic applications. Methods 2020, 177, 2–14. [Google Scholar] [CrossRef]
  77. Liu, Y.; Luo, J.; Chen, X.; Liu, W.; Chen, T. Cell Membrane Coating Technology: A Promising Strategy for Biomedical Applications. Nanomicro. Lett. 2019, 11, 100. [Google Scholar] [CrossRef] [Green Version]
  78. Bahmani, B.; Gong, H.; Luk, B.T.; Haushalter, K.J.; DeTeresa, E.; Previti, M.; Zhou, J.; Gao, W.; Bui, J.D.; Zhang, L.; et al. Intratumoral immunotherapy using platelet-cloaked nanoparticles enhances antitumor immunity in solid tumors. Nat. Commun. 2021, 12, 1999. [Google Scholar] [CrossRef] [PubMed]
  79. Wang, C.; Sun, W.; Ye, Y.; Hu, Q.; Bomba, H.N.; Gu, Z. In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. Nat. Biomed. Eng. 2017, 1, 11. [Google Scholar] [CrossRef]
  80. Hu, Q.; Li, H.; Archibong, E.; Chen, Q.; Ruan, H.; Ahn, S.; Dukhovlinova, E.; Kang, Y.; Wen, D.; Dotti, G.; et al. Inhibition of post-surgery tumour recurrence via a hydrogel releasing CAR-T cells and anti-PDL1-conjugated platelets. Nat. Biomed. Eng. 2021, 5, 1038–1047. [Google Scholar] [CrossRef]
  81. Lv, Y.; Li, F.; Wang, S.; Lu, G.; Bao, W.; Wang, Y.; Tian, Z.; Wei, W.; Ma, G. Near-infrared light-triggered platelet arsenal for combined photothermal-immunotherapy against cancer. Sci. Adv. 2021, 7, eabd7614. [Google Scholar] [CrossRef]
  82. Lu, Q.; Ye, H.; Wang, K.; Zhao, J.; Wang, H.; Song, J.; Fan, X.; Lu, Y.; Cao, L.; Wan, B.; et al. Bioengineered Platelets Combining Chemotherapy and Immunotherapy for Postsurgical Melanoma Treatment: Internal Core-Loaded Doxorubicin and External Surface-Anchored Anti-PD-L1 Antibody Backpacks. Nano Lett. 2022, 22, 3141–3150. [Google Scholar] [CrossRef] [PubMed]
  83. Fu, J.; Wang, D.; Mei, D.; Zhang, H.; Wang, Z.; He, B.; Dai, W.; Zhang, H.; Wang, X.; Zhang, Q. Macrophage mediated biomimetic delivery system for the treatment of lung metastasis of breast cancer. J. Control. Release 2015, 204, 11–19. [Google Scholar] [CrossRef] [PubMed]
  84. Wang, C.; Li, K.; Li, T.; Chen, Z.; Wen, Y.; Liu, X.; Jia, X.; Zhang, Y.; Xu, Y.; Han, M.; et al. Monocyte-mediated chemotherapy drug delivery in glioblastoma. Nanomedicine 2018, 13, 157–178. [Google Scholar] [CrossRef]
  85. Tang, K.; Zhang, Y.; Zhang, H.; Xu, P.; Liu, J.; Ma, J.; Lv, M.; Li, D.; Katirai, F.; Shen, G.X.; et al. Delivery of chemotherapeutic drugs in tumour cell-derived microparticles. Nat. Commun. 2012, 3, 1282. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Yanaihara, N.; Caplen, N.; Bowman, E.; Seike, M.; Kumamoto, K.; Yi, M.; Stephens, R.M.; Okamoto, A.; Yokota, J.; Tanaka, T.; et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006, 9, 189–198. [Google Scholar] [CrossRef] [Green Version]
  87. Saari, H.; Lazaro-Ibanez, E.; Viitala, T.; Vuorimaa-Laukkanen, E.; Siljander, P.; Yliperttula, M. Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells. J. Control. Release 2015, 220, 727–737. [Google Scholar] [CrossRef] [Green Version]
  88. Ohno, S.; Takanashi, M.; Sudo, K.; Ueda, S.; Ishikawa, A.; Matsuyama, N.; Fujita, K.; Mizutani, T.; Ohgi, T.; Ochiya, T.; et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol. Ther. 2013, 21, 185–191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Rivoltini, L.; Chiodoni, C.; Squarcina, P.; Tortoreto, M.; Villa, A.; Vergani, B.; Burdek, M.; Botti, L.; Arioli, I.; Cova, A.; et al. TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Armed Exosomes Deliver Proapoptotic Signals to Tumor Site. Clin. Cancer Res. 2016, 22, 3499–3512. [Google Scholar] [CrossRef] [Green Version]
  90. Hirsch, L.R.; Stafford, R.J.; Bankson, J.A.; Sershen, S.R.; Rivera, B.; Price, R.E.; Hazle, J.D.; Halas, N.J.; West, J.L. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc. Natl. Acad. Sci. USA 2003, 100, 13549–13554. [Google Scholar] [CrossRef] [Green Version]
  91. Huang, X.; Jain, P.K.; El-Sayed, I.H.; El-Sayed, M.A. Plasmonic photothermal therapy (PPTT) using gold nanoparticles. Lasers Med. Sci. 2008, 23, 217–228. [Google Scholar] [CrossRef] [PubMed]
  92. Korovin, M.S.; Fomenko, A.N. Application of nanodimensional particles and aluminum hydroxide nanostructures for cancer diagnosis and therapy. AIP Conf. Proc. 2017, 1882, 020036. [Google Scholar]
  93. Dykman, L.A.; Khlebtsov, N.G. Gold nanoparticles in biology and medicine: Recent advances and prospects. Acta Nat. 2011, 3, 34–55. [Google Scholar] [CrossRef] [Green Version]
  94. Sakthi Devi, R.; Girigoswami, A.; Siddharth, M.; Girigoswami, K. Applications of Gold and Silver Nanoparticles in Theranostics. Appl. Biochem. Biotechnol. 2022, 194, 4187–4219. [Google Scholar] [CrossRef] [PubMed]
  95. Yang, Y.; Hu, Y.; Du, H.; Ren, L.; Wang, H. Colloidal plasmonic gold nanoparticles and gold nanorings: Shape-dependent generation of singlet oxygen and their performance in enhanced photodynamic cancer therapy. Int. J. Nanomed. 2018, 13, 2065–2078. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Park, T.; Lee, S.; Amatya, R.; Cheong, H.; Moon, C.; Kwak, H.D.; Min, K.A.; Shin, M.C. ICG-Loaded PEGylated BSA-Silver Nanoparticles for Effective Photothermal Cancer Therapy. Int. J. Nanomed. 2020, 15, 5459–5471. [Google Scholar] [CrossRef]
  97. Teodor, E.D.; Radu, G.L. Phyto-synthesized Gold Nanoparticles as Antitumor Agents. Pharm. Nanotechnol. 2021, 9, 51–60. [Google Scholar] [CrossRef]
  98. Paiva-Santos, A.C.; Herdade, A.M.; Guerra, C.; Peixoto, D.; Pereira-Silva, M.; Zeinali, M.; Mascarenhas-Melo, F.; Paranhos, A.; Veiga, F. Plant-mediated green synthesis of metal-based nanoparticles for dermopharmaceutical and cosmetic applications. Int. J. Pharm. 2021, 597, 120311. [Google Scholar] [CrossRef]
  99. Vijayan, R.; Joseph, S.; Mathew, B. Anticancer, antimicrobial, antioxidant, and catalytic activities of green-synthesized silver and gold nanoparticles using Bauhinia purpurea leaf extract. Bioprocess Biosyst. Eng. 2019, 42, 305–319. [Google Scholar] [CrossRef]
  100. Naraginti, S.; Li, Y. Preliminary investigation of catalytic, antioxidant, anticancer and bactericidal activity of green synthesized silver and gold nanoparticles using Actinidia deliciosa. J. Photochem. Photobiol. B 2017, 170, 225–234. [Google Scholar] [CrossRef]
  101. Anand, K.; Tiloke, C.; Naidoo, P.; Chuturgoon, A.A. Phytonanotherapy for management of diabetes using green synthesis nanoparticles. J. Photochem. Photobiol. B 2017, 173, 626–639. [Google Scholar] [CrossRef] [PubMed]
  102. Baghbani-Arani, F.; Movagharnia, R.; Sharifian, A.; Salehi, S.; Shandiz, S.A.S. Photo-catalytic, anti-bacterial, and anti-cancer properties of phyto-mediated synthesis of silver nanoparticles from Artemisia tournefortiana Rchb extract. J. Photochem. Photobiol. B 2017, 173, 640–649. [Google Scholar] [CrossRef]
  103. Sharma, R.; Srivastava, N. Plant Mediated Silver Nanoparticles and Mode of Action in Cancer Therapy: A Review. Anticancer Agents Med. Chem. 2021, 21, 1793–1801. [Google Scholar] [CrossRef] [PubMed]
  104. Barkat, A.; Beg, S.; Panda, S.K.; Alharbi, K.S.; Rahman, M.; Ahmed, F.J. Functionalized mesoporous silica nanoparticles in anticancer therapeutics. Semin. Cancer Biol. 2021, 69, 365–375. [Google Scholar] [CrossRef]
  105. Tarn, D.; Ashley, C.E.; Xue, M.; Carnes, E.C.; Zink, J.I.; Brinker, C.J. Mesoporous silica nanoparticle nanocarriers: Biofunctionality and biocompatibility. Acc. Chem. Res. 2013, 46, 792–801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Baek, S.; Singh, R.K.; Khanal, D.; Patel, K.D.; Lee, E.J.; Leong, K.W.; Chrzanowski, W.; Kim, H.W. Smart multifunctional drug delivery towards anticancer therapy harmonized in mesoporous nanoparticles. Nanoscale 2015, 7, 14191–14216. [Google Scholar] [CrossRef]
  107. Kumar, P.; Tambe, P.; Paknikar, K.M.; Gajbhiye, V. Folate/N-acetyl glucosamine conjugated mesoporous silica nanoparticles for targeting breast cancer cells: A comparative study. Colloids Surf. B Biointerfaces 2017, 156, 203–212. [Google Scholar] [CrossRef]
  108. Gu, F.X.; Karnik, R.; Wang, A.Z.; Alexis, F.; Levy-Nissenbaum, E.; Hong, S.; Langer, R.S.; Farokhzad, O.C. Targeted nanoparticles for cancer therapy. Nano Today 2007, 2, 14–21. [Google Scholar] [CrossRef]
  109. Hong, E.J.; Choi, D.G.; Shim, M.S. Targeted and effective photodynamic therapy for cancer using functionalized nanomaterials. Acta Pharm. Sin. B 2016, 6, 297–307. [Google Scholar] [CrossRef] [Green Version]
  110. Apostolova, N.; Victor, V.M. Molecular strategies for targeting antioxidants to mitochondria: Therapeutic implications. Antioxid. Redox Signal. 2015, 22, 686–729. [Google Scholar] [CrossRef] [Green Version]
  111. Tuo, J.; Xie, Y.; Song, J.; Chen, Y.; Guo, Q.; Liu, X.; Ni, X.; Xu, D.; Huang, H.; Yin, S.; et al. Development of a novel berberine-mediated mitochondria-targeting nano-platform for drug-resistant cancer therapy. J. Mater. Chem. B 2016, 4, 6856–6864. [Google Scholar] [CrossRef]
  112. Lo, Y.L.; Wang, C.S.; Chen, Y.C.; Wang, T.Y.; Chang, Y.H.; Chen, C.J.; Yang, C.P. Mitochondrion-Directed Nanoparticles Loaded with a Natural Compound and a microRNA for Promoting Cancer Cell Death via the Modulation of Tumor Metabolism and Mitochondrial Dynamics. Pharmaceutics 2020, 12, 756. [Google Scholar] [CrossRef] [PubMed]
  113. Zhu, Y.; Liang, J.; Gao, C.; Wang, A.; Xia, J.; Hong, C.; Zhong, Z.; Zuo, Z.; Kim, J.; Ren, H.; et al. Multifunctional ginsenoside Rg3-based liposomes for glioma targeting therapy. J. Control. Release 2021, 330, 641–657. [Google Scholar] [CrossRef] [PubMed]
  114. Li, J.; Gao, Y.; Liu, S.; Cai, J.; Zhang, Q.; Li, K.; Liu, Z.; Shi, M.; Wang, J.; Cui, H. Aptamer-functionalized quercetin thermosensitive liposomes for targeting drug delivery and antitumor therapy. Biomed. Mater. 2022, 17, 65003. [Google Scholar] [CrossRef]
  115. Zheng, Z.; Zhang, J.; Jiang, J.; He, Y.; Zhang, W.; Mo, X.; Kang, X.; Xu, Q.; Wang, B.; Huang, Y. Remodeling tumor immune microenvironment (TIME) for glioma therapy using multi-targeting liposomal codelivery. J. Immunother. Cancer 2020, 8, e000207. [Google Scholar] [CrossRef] [PubMed]
  116. Li, L.; Wang, Q.; Zhang, X.; Luo, L.; He, Y.; Zhu, R.; Gao, D. Dual-targeting liposomes for enhanced anticancer effect in somatostatin receptor II-positive tumor model. Nanomedicine 2018, 13, 2155–2169. [Google Scholar] [CrossRef] [PubMed]
  117. Gai, C.; Liu, C.; Wu, X.; Yu, M.; Zheng, J.; Zhang, W.; Lv, S.; Li, W. MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells. Cell Death Dis. 2020, 11, 751. [Google Scholar] [CrossRef]
  118. Zhang, J.; Hu, X.; Zheng, G.; Yao, H.; Liang, H. In vitro and in vivo antitumor effects of lupeol-loaded galactosylated liposomes. Drug Deliv. 2021, 28, 709–718. [Google Scholar] [CrossRef]
  119. Torchilin, V.P. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 2005, 4, 145–160. [Google Scholar] [CrossRef]
  120. Meng, J.; Guo, F.; Xu, H.; Liang, W.; Wang, C.; Yang, X.D. Combination Therapy using Co-encapsulated Resveratrol and Paclitaxel in Liposomes for Drug Resistance Reversal in Breast Cancer Cells in vivo. Sci. Rep. 2016, 6, 22390. [Google Scholar] [CrossRef] [Green Version]
  121. Huang, L.; Sun, Z.; Shen, Q.; Huang, Z.; Wang, S.; Yang, N.; Li, G.; Wu, Q.; Wang, W.; Li, L.; et al. Rational design of nanocarriers for mitochondria-targeted drug delivery. Chin. Chem. Lett. 2022, 33, 4146–4156. [Google Scholar] [CrossRef]
  122. Pijeira, M.S.O.; Viltres, H.; Kozempel, J.; Sakmár, M.; Vlk, M.; İlem-Özdemir, D.; Ekinci, M.; Srinivasan, S.; Rajabzadeh, A.R.; Ricci-Junior, E.; et al. Radiolabeled nanomaterials for biomedical applications: Radiopharmacy in the era of nanotechnology. EJNMMI Radiopharm. Chem. 2022, 7, 8. [Google Scholar] [CrossRef] [PubMed]
  123. Ghasemi, S.; Owrang, M.; Javaheri, F.; Farjadian, F. Spermine Modified PNIPAAm Nano-Hydrogel Serving as Thermo Responsive System for Delivery of Cisplatin. Macromol. Res. 2022, 30, 314–324. [Google Scholar] [CrossRef]
  124. He, Q.; Yan, R.; Hou, W.; Wang, H.; Tian, Y. A pH-Responsive Zwitterionic Polyurethane Prodrug as Drug Delivery System for Enhanced Cancer Therapy. Molecules 2021, 26, 74. [Google Scholar] [CrossRef] [PubMed]
  125. Duan, X.; Bai, T.; Du, J.; Kong, J. One-pot synthesis of glutathione-responsive amphiphilic drug self-delivery micelles of doxorubicin-disulfide-methoxy polyethylene glycol for tumor therapy. J. Mater. Chem. B 2018, 6, 39–43. [Google Scholar] [CrossRef] [PubMed]
  126. Chen, C.Y.; Kim, T.H.; Wu, W.C.; Huang, C.M.; Wei, H.; Mount, C.W.; Tian, Y.; Jang, S.H.; Pun, S.H.; Jen, A.K. pH-dependent, thermosensitive polymeric nanocarriers for drug delivery to solid tumors. Biomaterials 2013, 34, 4501–4509. [Google Scholar] [CrossRef] [Green Version]
  127. Alotaibi, K.M.; Almethen, A.A.; Beagan, A.M.; Alfhaid, L.H.; Ahamed, M.; El-Toni, A.M.; Alswieleh, A.M. Poly(oligo(ethylene glycol) methyl ether methacrylate) Capped pH-Responsive Poly(2-(diethylamino)ethyl methacrylate) Brushes Grafted on Mesoporous Silica Nanoparticles as Nanocarrier. Polymers 2021, 13, 823. [Google Scholar] [CrossRef]
  128. Hou, S.L.; Chen, S.S.; Huang, Z.J.; Lu, Q.H. Dual-responsive polyphosphazene as a common platform for highly efficient drug self-delivery. J. Mater. Chem. B 2019, 7, 4319–4327. [Google Scholar] [CrossRef]
  129. Liu, Y.; Xie, J.; Zhao, X.; Zhang, Y.; Zhong, Z.; Deng, C. A polymeric IDO inhibitor based on poly(ethylene glycol)-b-poly(L-tyrosine-co-1-methyl-D-tryptophan) enables facile trident cancer immunotherapy. Biomater. Sci. 2022, 10, 5731–5743. [Google Scholar] [CrossRef]
  130. Kalhapure, R.S.; Renukuntla, J. Thermo- and pH dual responsive polymeric micelles and nanoparticles. Chem. Biol. Interact. 2018, 295, 20–37. [Google Scholar] [CrossRef]
  131. Liu, J.; Zhang, B.; Luo, Z.; Ding, X.; Li, J.; Dai, L.; Zhou, J.; Zhao, X.; Ye, J.; Cai, K. Enzyme responsive mesoporous silica nanoparticles for targeted tumor therapy in vitro and in vivo. Nanoscale 2015, 7, 3614–3626. [Google Scholar] [CrossRef]
  132. Li, B.; Pang, S.; Li, X.; Li, Y. PH and redox dual-responsive polymeric micelles with charge conversion for paclitaxel delivery. J. Biomater. Sci. Polym. Ed. 2020, 31, 2078–2093. [Google Scholar] [CrossRef]
  133. Whitlow, J.; Pacelli, S.; Paul, A. Polymeric Nanohybrids as a New Class of Therapeutic Biotransporters. Macromol. Chem. Phys. 2016, 217, 1245–1259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Zhang, L.; Qin, Y.; Zhang, Z.; Fan, F.; Huang, C.; Lu, L.; Wang, H.; Jin, X.; Zhao, H.; Kong, D.; et al. Dual pH/reduction-responsive hybrid polymeric micelles for targeted chemo-photothermal combination therapy. Acta Biomater. 2018, 75, 371–385. [Google Scholar] [CrossRef] [PubMed]
  135. Mottaghitalab, F.; Farokhi, M.; Fatahi, Y.; Atyabi, F.; Dinarvand, R. New insights into designing hybrid nanoparticles for lung cancer: Diagnosis and treatment. J. Control. Release 2019, 295, 250–267. [Google Scholar] [CrossRef]
  136. Mignani, S.; Shi, X.; Cena, V.; Rodrigues, J.; Tomas, H.; Majoral, J.P. Engineered non-invasive functionalized dendrimer/dendron-entrapped/complexed gold nanoparticles as a novel class of theranostic (radio)pharmaceuticals in cancer therapy. J. Control. Release 2021, 332, 346–366. [Google Scholar] [CrossRef]
  137. Pfaff, A.; Schallon, A.; Ruhland, T.M.; Majewski, A.P.; Schmalz, H.; Freitag, R.; Muller, A.H. Magnetic and fluorescent glycopolymer hybrid nanoparticles for intranuclear optical imaging. Biomacromolecules 2011, 12, 3805–3811. [Google Scholar] [CrossRef] [PubMed]
  138. Wang, H.; Zheng, L.; Peng, C.; Shen, M.; Shi, X.; Zhang, G. Folic acid-modified dendrimer-entrapped gold nanoparticles as nanoprobes for targeted CT imaging of human lung adencarcinoma. Biomaterials 2013, 34, 470–480. [Google Scholar] [CrossRef] [PubMed]
  139. Elhabak, M.; Osman, R.; Mohamed, M.; El-Borady, O.M.; Awad, G.A.S.; Mortada, N. Near IR responsive targeted integrated lipid polymer nanoconstruct for enhanced magnolol cytotoxicity in breast cancer. Sci. Rep. 2020, 10, 8771. [Google Scholar] [CrossRef]
  140. Hadinoto, K.; Sundaresan, A.; Cheow, W.S. Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform: A review. Eur. J. Pharm. Biopharm. 2013, 85, 427–443. [Google Scholar] [CrossRef]
  141. Gautier, J.; Allard-Vannier, E.; Herve-Aubert, K.; Souce, M.; Chourpa, I. Design strategies of hybrid metallic nanoparticles for theragnostic applications. Nanotechnology 2013, 24, 432002. [Google Scholar] [CrossRef] [PubMed]
  142. Ma, Z.; Li, X.; Jia, X.; Bai, J.; Jiang, X. Folate-Conjugated Polylactic Acid-Silica Hybrid Nanoparticles as Degradable Carriers for Targeted Drug Delivery, On-Demand Release and Simultaneous Self-Clearance. Chempluschem 2016, 81, 652–659. [Google Scholar] [CrossRef] [PubMed]
  143. Kaczmarek, J.C.; Patel, A.K.; Kauffman, K.J.; Fenton, O.S.; Webber, M.J.; Heartlein, M.W.; DeRosa, F.; Anderson, D.G. Polymer-Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs. Angew. Chem. Int. Ed. Engl. 2016, 55, 13808–13812. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Chen, H.; Ren, X.; Xu, S.; Zhang, D.; Han, T. Optimization of Lipid Nanoformulations for Effective mRNA Delivery. Int. J. Nanomed. 2022, 17, 2893–2905. [Google Scholar] [CrossRef]
  145. Fraix, A.; Conte, C.; Gazzano, E.; Riganti, C.; Quaglia, F.; Sortino, S. Overcoming Doxorubicin Resistance with Lipid-Polymer Hybrid Nanoparticles Photoreleasing Nitric Oxide. Mol. Pharm. 2020, 17, 2135–2144. [Google Scholar] [CrossRef]
  146. Guo, Y.; Wang, D.; Song, Q.; Wu, T.; Zhuang, X.; Bao, Y.; Kong, M.; Qi, Y.; Tan, S.; Zhang, Z. Erythrocyte Membrane-Enveloped Polymeric Nanoparticles as Nanovaccine for Induction of Antitumor Immunity against Melanoma. ACS Nano 2015, 9, 6918–6933. [Google Scholar] [CrossRef]
  147. Mandal, B.; Bhattacharjee, H.; Mittal, N.; Sah, H.; Balabathula, P.; Thoma, L.A.; Wood, G.C. Core-shell-type lipid-polymer hybrid nanoparticles as a drug delivery platform. Nanomedicine 2013, 9, 474–491. [Google Scholar] [CrossRef]
  148. Reuven, E.M.; Leviatan Ben-Arye, S.; Yu, H.; Duchi, R.; Perota, A.; Conchon, S.; Bachar Abramovitch, S.; Soulillou, J.P.; Galli, C.; Chen, X.; et al. Biomimetic Glyconanoparticle Vaccine for Cancer Immunotherapy. ACS Nano 2019, 13, 2936–2947. [Google Scholar] [CrossRef]
  149. Peng, H.; Xu, Z.; Wang, Y.; Feng, N.; Yang, W.; Tang, J. Biomimetic Mesoporous Silica Nanoparticles for Enhanced Blood Circulation and Cancer Therapy. ACS Appl. Bio Mater. 2020, 3, 7849–7857. [Google Scholar] [CrossRef]
  150. Pitchaimani, A.; Nguyen, T.D.T.; Aryal, S. Natural killer cell membrane infused biomimetic liposomes for targeted tumor therapy. Biomaterials 2018, 160, 124–137. [Google Scholar] [CrossRef]
  151. Parodi, A.; Molinaro, R.; Sushnitha, M.; Evangelopoulos, M.; Martinez, J.O.; Arrighetti, N.; Corbo, C.; Tasciotti, E. Bio-inspired engineering of cell- and virus-like nanoparticles for drug delivery. Biomaterials 2017, 147, 155–168. [Google Scholar] [CrossRef] [PubMed]
  152. Han, Y.; Pan, H.; Li, W.; Chen, Z.; Ma, A.; Yin, T.; Liang, R.; Chen, F.; Ma, Y.; Jin, Y.; et al. T Cell Membrane Mimicking Nanoparticles with Bioorthogonal Targeting and Immune Recognition for Enhanced Photothermal Therapy. Adv. Sci. 2019, 6, 1900251. [Google Scholar] [CrossRef] [PubMed]
  153. Xia, Q.; Zhang, Y.; Li, Z.; Hou, X.; Feng, N. Red blood cell membrane-camouflaged nanoparticles: A novel drug delivery system for antitumor application. Acta Pharm. Sin. B 2019, 9, 675–689. [Google Scholar] [CrossRef] [PubMed]
  154. Zhang, Y.; Liu, Y.; Zhang, W.; Tang, Q.; Zhou, Y.; Li, Y.; Rong, T.; Wang, H.; Chen, Y. Isolated cell-bound membrane vesicles (CBMVs) as a novel class of drug nanocarriers. J. Nanobiotechnol. 2020, 18, 69. [Google Scholar] [CrossRef]
  155. Hu, C.M.; Zhang, L.; Aryal, S.; Cheung, C.; Fang, R.H.; Zhang, L. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc. Natl. Acad. Sci. USA 2011, 108, 10980–10985. [Google Scholar] [CrossRef] [Green Version]
  156. Huang, Y.; Mei, C.; Tian, Y.; Nie, T.; Liu, Z.; Chen, T. Bioinspired tumor-homing nanosystem for precise cancer therapy via reprogramming of tumor-associated macrophages. NPG Asia Mater. 2018, 10, 1002–1015. [Google Scholar] [CrossRef] [Green Version]
  157. Xu, C.; Liu, W.; Hu, Y.; Li, W.; Di, W. Bioinspired tumor-homing nanoplatform for co-delivery of paclitaxel and siRNA-E7 to HPV-related cervical malignancies for synergistic therapy. Theranostics 2020, 10, 3325–3339. [Google Scholar] [CrossRef]
  158. Liu, J.; Wu, F.; Zhou, H. Macrophage-derived exosomes in cancers: Biogenesis, functions and therapeutic applications. Immunol. Lett. 2020, 227, 102–108. [Google Scholar] [CrossRef]
  159. Zhang, Y.; Guoqiang, L.; Sun, M.; Lu, X. Targeting and exploitation of tumor-associated neutrophils to enhance immunotherapy and drug delivery for cancer treatment. Cancer Biol. Med. 2020, 17, 32–43. [Google Scholar] [CrossRef]
  160. Zhao, L.; Gu, C.; Gan, Y.; Shao, L.; Chen, H.; Zhu, H. Exosome-mediated siRNA delivery to suppress postoperative breast cancer metastasis. J. Control. Release 2020, 318, 1–15. [Google Scholar] [CrossRef]
  161. Zuo, B.; Qi, H.; Lu, Z.; Chen, L.; Sun, B.; Yang, R.; Zhang, Y.; Liu, Z.; Gao, X.; You, A.; et al. Alarmin-painted exosomes elicit persistent antitumor immunity in large established tumors in mice. Nat. Commun. 2020, 11, 1790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. Zhu, Q.; Ling, X.; Yang, Y.; Zhang, J.; Li, Q.; Niu, X.; Hu, G.; Chen, B.; Li, H.; Wang, Y.; et al. Embryonic Stem Cells-Derived Exosomes Endowed with Targeting Properties as Chemotherapeutics Delivery Vehicles for Glioblastoma Therapy. Adv. Sci. 2019, 6, 1801899. [Google Scholar] [CrossRef]
  163. Liu, Y.; Guo, J.; Huang, L. Modulation of tumor microenvironment for immunotherapy: Focus on nanomaterial-based strategies. Theranostics 2020, 10, 3099–3117. [Google Scholar] [CrossRef] [PubMed]
  164. Phuengkham, H.; Ren, L.; Shin, I.W.; Lim, Y.T. Nanoengineered Immune Niches for Reprogramming the Immunosuppressive Tumor Microenvironment and Enhancing Cancer Immunotherapy. Adv. Mater. 2019, 31, e1803322. [Google Scholar] [CrossRef]
  165. Xiao, Y.; Yu, D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol. Ther. 2021, 221, 107753. [Google Scholar] [CrossRef] [PubMed]
  166. Upreti, M.; Jyoti, A.; Sethi, P. Tumor microenvironment and nanotherapeutics. Transl. Cancer Res. 2013, 2, 309–319. [Google Scholar] [CrossRef] [PubMed]
  167. Jiang, T.; Zhang, B.; Shen, S.; Tuo, Y.; Luo, Z.; Hu, Y.; Pang, Z.; Jiang, X. Tumor Microenvironment Modulation by Cyclopamine Improved Photothermal Therapy of Biomimetic Gold Nanorods for Pancreatic Ductal Adenocarcinomas. ACS Appl. Mater. Interfaces 2017, 9, 31497–31508. [Google Scholar] [CrossRef]
  168. Zhang, D.; Feng, F.; Li, Q.; Wang, X.; Yao, L. Nanopurpurin-based photodynamic therapy destructs extracellular matrix against intractable tumor metastasis. Biomaterials 2018, 173, 22–33. [Google Scholar] [CrossRef]
  169. Paardekooper, L.M.; Vos, W.; van den Bogaart, G. Oxygen in the tumor microenvironment: Effects on dendritic cell function. Oncotarget 2019, 10, 883–896. [Google Scholar] [CrossRef] [Green Version]
  170. Balkwill, F.R.; Capasso, M.; Hagemann, T. The tumor microenvironment at a glance. J. Cell Sci. 2012, 125, 5591–5596. [Google Scholar] [CrossRef] [Green Version]
  171. Zhang, M.; Zhao, Y.; Ma, H.; Sun, Y.; Cao, J. How to improve photodynamic therapy-induced antitumor immunity for cancer treatment? Theranostics 2022, 12, 4629–4655. [Google Scholar] [CrossRef]
  172. Gupta, Y.H.; Khanom, A.; Acton, S.E. Control of Dendritic Cell Function Within the Tumour Microenvironment. Front. Immunol. 2022, 13, 733800. [Google Scholar] [CrossRef] [PubMed]
  173. Yang, C.; Liu, Y.; He, Y.; Du, Y.; Wang, W.; Shi, X.; Gao, F. The use of HA oligosaccharide-loaded nanoparticles to breach the endogenous hyaluronan glycocalyx for breast cancer therapy. Biomaterials 2013, 34, 6829–6838. [Google Scholar] [CrossRef] [PubMed]
  174. Zhang, Y.; Han, X.; Nie, G. Responsive and activable nanomedicines for remodeling the tumor microenvironment. Nat. Protoc. 2021, 16, 405–430. [Google Scholar] [CrossRef] [PubMed]
  175. Huels, D.J.; Medema, J.P. Think About the Environment: Cellular Reprogramming by the Extracellular Matrix. Cell Stem Cell 2018, 22, 7–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  176. Hawk, M.A.; Gorsuch, C.L.; Fagan, P.; Lee, C.; Kim, S.E.; Hamann, J.C.; Mason, J.A.; Weigel, K.J.; Tsegaye, M.A.; Shen, L.; et al. RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells. Nat. Cell Biol. 2018, 20, 272–284. [Google Scholar] [CrossRef] [PubMed]
  177. Kovacs, D.; Igaz, N.; Marton, A.; Ronavari, A.; Belteky, P.; Bodai, L.; Spengler, G.; Tiszlavicz, L.; Razga, Z.; Hegyi, P.; et al. Core-shell nanoparticles suppress metastasis and modify the tumour-supportive activity of cancer-associated fibroblasts. J. Nanobiotechnol. 2020, 18, 18. [Google Scholar] [CrossRef]
  178. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 2016, 16, 582–598. [Google Scholar] [CrossRef]
  179. Zhou, H.; Fan, Z.; Deng, J.; Lemons, P.K.; Arhontoulis, D.C.; Bowne, W.B.; Cheng, H. Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy. Nano Lett. 2016, 16, 3268–3277. [Google Scholar] [CrossRef]
  180. Gong, H.; Chao, Y.; Xiang, J.; Han, X.; Song, G.; Feng, L.; Liu, J.; Yang, G.; Chen, Q.; Liu, Z. Hyaluronidase To Enhance Nanoparticle-Based Photodynamic Tumor Therapy. Nano Lett. 2016, 16, 2512–2521. [Google Scholar] [CrossRef]
  181. Guan, X.; Chen, J.; Hu, Y.; Lin, L.; Sun, P.; Tian, H.; Chen, X. Highly enhanced cancer immunotherapy by combining nanovaccine with hyaluronidase. Biomaterials 2018, 171, 198–206. [Google Scholar] [CrossRef] [PubMed]
  182. Ji, T.; Lang, J.; Wang, J.; Cai, R.; Zhang, Y.; Qi, F.; Zhang, L.; Zhao, X.; Wu, W.; Hao, J.; et al. Designing Liposomes To Suppress Extracellular Matrix Expression To Enhance Drug Penetration and Pancreatic Tumor Therapy. ACS Nano 2017, 11, 8668–8678. [Google Scholar] [CrossRef] [PubMed]
  183. Guo, J.; Yu, Z.; Sun, D.; Zou, Y.; Liu, Y.; Huang, L. Two nanoformulations induce reactive oxygen species and immunogenetic cell death for synergistic chemo-immunotherapy eradicating colorectal cancer and hepatocellular carcinoma. Mol. Cancer 2021, 20, 10. [Google Scholar] [CrossRef] [PubMed]
  184. Han, S.; Bi, S.; Guo, T.; Sun, D.; Zou, Y.; Wang, L.; Song, L.; Chu, D.; Liao, A.; Song, X.; et al. Nano co-delivery of Plumbagin and Dihydrotanshinone I reverses immunosuppressive TME of liver cancer. J. Control. Release 2022, 348, 250–263. [Google Scholar] [CrossRef]
  185. Dudek, A.M.; Garg, A.D.; Krysko, D.V.; De Ruysscher, D.; Agostinis, P. Inducers of immunogenic cancer cell death. Cytokine Growth Factor Rev. 2013, 24, 319–333. [Google Scholar] [CrossRef]
  186. Yu, X.; Fang, C.; Zhang, K.; Su, C. Recent Advances in Nanoparticles-Based Platforms Targeting the PD-1/PD-L1 Pathway for Cancer Treatment. Pharmaceutics 2022, 14, 1581. [Google Scholar] [CrossRef]
  187. Zhang, X.; Wang, C.; Wang, J.; Hu, Q.; Langworthy, B.; Ye, Y.; Sun, W.; Lin, J.; Wang, T.; Fine, J.; et al. PD-1 Blockade Cellular Vesicles for Cancer Immunotherapy. Adv. Mater. 2018, 30, e1707112. [Google Scholar] [CrossRef]
  188. Hu, Q.; Sun, W.; Wang, J.; Ruan, H.; Zhang, X.; Ye, Y.; Shen, S.; Wang, C.; Lu, W.; Cheng, K.; et al. Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy. Nat. Biomed. Eng. 2018, 2, 831–840. [Google Scholar] [CrossRef]
  189. Komohara, Y.; Fujiwara, Y.; Ohnishi, K.; Takeya, M. Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv. Drug Deliv. Rev. 2016, 99, 180–185. [Google Scholar] [CrossRef]
  190. Ngambenjawong, C.; Gustafson, H.H.; Pun, S.H. Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Adv. Drug Deliv. Rev. 2017, 114, 206–221. [Google Scholar] [CrossRef] [Green Version]
  191. Peranzoni, E.; Lemoine, J.; Vimeux, L.; Feuillet, V.; Barrin, S.; Kantari-Mimoun, C.; Bercovici, N.; Guerin, M.; Biton, J.; Ouakrim, H.; et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proc. Natl. Acad. Sci. USA 2018, 115, E4041–E4050. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  192. Xia, Y.; Rao, L.; Yao, H.; Wang, Z.; Ning, P.; Chen, X. Engineering Macrophages for Cancer Immunotherapy and Drug Delivery. Adv. Mater. 2020, 32, e2002054. [Google Scholar] [CrossRef] [PubMed]
  193. Chen, Q.; Wang, C.; Zhang, X.; Chen, G.; Hu, Q.; Li, H.; Wang, J.; Wen, D.; Zhang, Y.; Lu, Y.; et al. In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment. Nat. Nanotechnol. 2019, 14, 89–97. [Google Scholar] [CrossRef] [PubMed]
  194. Shi, C.; Liu, T.; Guo, Z.; Zhuang, R.; Zhang, X.; Chen, X. Reprogramming Tumor-Associated Macrophages by Nanoparticle-Based Reactive Oxygen Species Photogeneration. Nano Lett. 2018, 18, 7330–7342. [Google Scholar] [CrossRef] [PubMed]
  195. Riera-Domingo, C.; Audigé, A.; Granja, S.; Cheng, W.C.; Ho, P.C.; Baltazar, F.; Stockmann, C.; Mazzone, M. Immunity, Hypoxia, and Metabolism-the Ménage à Trois of Cancer: Implications for Immunotherapy. Physiol. Rev. 2020, 100, 1–102. [Google Scholar] [CrossRef] [PubMed]
  196. Lu, L.; Barbi, J.; Pan, F. The regulation of immune tolerance by FOXP3. Nat. Rev. Immunol. 2017, 17, 703–717. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Sun, Y.; Li, Y.; Shi, S.; Dong, C. Exploiting a New Approach to Destroy the Barrier of Tumor Microenvironment: Nano-Architecture Delivery Systems. Molecules 2021, 26, 2703. [Google Scholar] [CrossRef]
  198. Ou, W.; Thapa, R.K.; Jiang, L.; Soe, Z.C.; Gautam, M.; Chang, J.H.; Jeong, J.H.; Ku, S.K.; Choi, H.G.; Yong, C.S.; et al. Regulatory T cell-targeted hybrid nanoparticles combined with immuno-checkpoint blockage for cancer immunotherapy. J. Control. Release 2018, 281, 84–96. [Google Scholar] [CrossRef]
  199. Cheng, K.; Ding, Y.; Zhao, Y.; Ye, S.; Zhao, X.; Zhang, Y.; Ji, T.; Wu, H.; Wang, B.; Anderson, G.J.; et al. Sequentially Responsive Therapeutic Peptide Assembling Nanoparticles for Dual-Targeted Cancer Immunotherapy. Nano Lett. 2018, 18, 3250–3258. [Google Scholar] [CrossRef]
  200. Hou, L.; Liu, Q.; Shen, L.; Liu, Y.; Zhang, X.; Chen, F.; Huang, L. Nano-delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in desmoplastic melanoma. Theranostics 2018, 8, 3781–3796. [Google Scholar] [CrossRef]
  201. Cecchini, A.; Raffa, V.; Canfarotta, F.; Signore, G.; Piletsky, S.; MacDonald, M.P.; Cuschieri, A. In Vivo Recognition of Human Vascular Endothelial Growth Factor by Molecularly Imprinted Polymers. Nano Lett. 2017, 17, 2307–2312. [Google Scholar] [CrossRef] [Green Version]
  202. Becker, H.M.; Deitmer, J.W. Transport Metabolons and Acid/Base Balance in Tumor Cells. Cancers 2020, 12, 899. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  203. Imtiyaz, Z.; He, J.; Leng, Q.; Agrawal, A.K.; Mixson, A.J. pH-Sensitive Targeting of Tumors with Chemotherapy-Laden Nanoparticles: Progress and Challenges. Pharmaceutics 2022, 14, 2427. [Google Scholar] [CrossRef] [PubMed]
  204. Siriwibool, S.; Kaekratoke, N.; Chansaenpak, K.; Siwawannapong, K.; Panajapo, P.; Sagarik, K.; Noisa, P.; Lai, R.Y.; Kamkaew, A. Near-Infrared Fluorescent pH Responsive Probe for Targeted Photodynamic Cancer Therapy. Sci. Rep. 2020, 10, 1283. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  205. Som, A.; Raliya, R.; Tian, L.; Akers, W.; Ippolito, J.E.; Singamaneni, S.; Biswas, P.; Achilefu, S. Monodispersed calcium carbonate nanoparticles modulate local pH and inhibit tumor growth in vivo. Nanoscale 2016, 8, 12639–12647. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  206. Xu, X.X.; Chen, S.Y.; Yi, N.B.; Li, X.; Chen, S.L.; Lei, Z.; Cheng, D.B.; Sun, T. Research progress on tumor hypoxia-associative nanomedicine. J. Control. Release 2022, 350, 829–840. [Google Scholar] [CrossRef] [PubMed]
  207. Chen, J.; Luo, H.; Liu, Y.; Zhang, W.; Li, H.; Luo, T.; Zhang, K.; Zhao, Y.; Liu, J. Oxygen-Self-Produced Nanoplatform for Relieving Hypoxia and Breaking Resistance to Sonodynamic Treatment of Pancreatic Cancer. ACS Nano 2017, 11, 12849–12862. [Google Scholar] [CrossRef]
  208. Zhao, P.; Zheng, M.; Luo, Z.; Fan, X.; Sheng, Z.; Gong, P.; Chen, Z.; Zhang, B.; Ni, D.; Ma, Y.; et al. Oxygen Nanocarrier for Combined Cancer Therapy: Oxygen-Boosted ATP-Responsive Chemotherapy with Amplified ROS Lethality. Adv. Healthc. Mater. 2016, 5, 2161–2167. [Google Scholar] [CrossRef]
  209. Tian, H.; Luo, Z.; Liu, L.; Zheng, M.; Chen, Z.; Ma, A.; Liang, R.; Han, Z.; Lu, C.; Cai, L. Cancer Cell Membrane-Biomimetic Oxygen Nanocarrier for Breaking Hypoxia-Induced Chemoresistance. Adv. Funct. Mater. 2017, 27, 1703197. [Google Scholar] [CrossRef]
  210. Song, G.; Ji, C.; Liang, C.; Song, X.; Yi, X.; Dong, Z.; Yang, K.; Liu, Z. TaOx decorated perfluorocarbon nanodroplets as oxygen reservoirs to overcome tumor hypoxia and enhance cancer radiotherapy. Biomaterials 2017, 112, 257–263. [Google Scholar] [CrossRef]
  211. Chen, M.; Liu, D.; Liu, F.; Wu, Y.; Peng, X.; Song, F. Recent advances of redox-responsive nanoplatforms for tumor theranostics. J. Control. Release 2021, 332, 269–284. [Google Scholar] [CrossRef]
  212. Guan, X.; Yin, H.H.; Xu, X.H.; Xu, G.; Zhang, Y.; Zhou, B.G.; Yue, W.W.; Liu, C.; Sun, L.P.; Xu, H.X.; et al. Tumor Metabolism-Engineered Composite Nanoplatforms Potentiate Sonodynamic Therapy via Reshaping Tumor Microenvironment and Facilitating Electron–Hole Pairs’ Separation. Adv. Funct. Mater. 2020, 30, 2000326. [Google Scholar] [CrossRef]
  213. Hu, B.; Yu, M.; Ma, X.; Sun, J.; Liu, C.; Wang, C.; Wu, S.; Fu, P.Y.; Yang, Z.; He, Y.; et al. Interferon-a potentiates anti-PD-1 efficacy by remodeling glucose metabolism in the hepatocellular carcinoma microenvironment. Cancer Discov. 2022, 12, 1718–1741. [Google Scholar] [CrossRef]
  214. Wei, Z.; Zhang, X.; Yong, T.; Bie, N.; Zhan, G.; Li, X.; Liang, Q.; Li, J.; Yu, J.; Huang, G.; et al. Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles. Nat. Commun. 2021, 12, 440. [Google Scholar] [CrossRef]
  215. Dai, Q.; Wilhelm, S.; Ding, D.; Syed, A.M.; Sindhwani, S.; Zhang, Y.; Chen, Y.Y.; MacMillan, P.; Chan, W.C.W. Quantifying the Ligand-Coated Nanoparticle Delivery to Cancer Cells in Solid Tumors. ACS Nano 2018, 12, 8423–8435. [Google Scholar] [CrossRef]
Figure 1. The inorganic nanoparticles (include gold NPs, silver NPs, and silica NPs) were designed for anti-tumor treatment via photodynamic, photothermal, and chemotherapy.
Figure 1. The inorganic nanoparticles (include gold NPs, silver NPs, and silica NPs) were designed for anti-tumor treatment via photodynamic, photothermal, and chemotherapy.
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Figure 2. Liposomes co-loading dual-drugs or multi-drugs were prepared for targeting tumor sites and enhancing anticancer effects.
Figure 2. Liposomes co-loading dual-drugs or multi-drugs were prepared for targeting tumor sites and enhancing anticancer effects.
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Figure 3. Targeted and responsive polymer nanoparticles design and targeted therapy.
Figure 3. Targeted and responsive polymer nanoparticles design and targeted therapy.
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Figure 4. The design and composition of hybrid nanocarriers.
Figure 4. The design and composition of hybrid nanocarriers.
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Figure 5. Specific-targeted modified biomimetic and natural nanocarriers for cancer targeting therapy.
Figure 5. Specific-targeted modified biomimetic and natural nanocarriers for cancer targeting therapy.
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Figure 6. Schematic of nanocarrier-strategies for reprogramming the TME. The strategies of the cancer therapy involved three pathways: (i) NP for destroying extracellular matrix (ECM); (ii) NP for activating immunostimulatory cells; (iii) NP for regulating immunosuppressive factors.
Figure 6. Schematic of nanocarrier-strategies for reprogramming the TME. The strategies of the cancer therapy involved three pathways: (i) NP for destroying extracellular matrix (ECM); (ii) NP for activating immunostimulatory cells; (iii) NP for regulating immunosuppressive factors.
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Table 1. Development and clinical studies of various types of representative nanocarriers for cancer therapy.
Table 1. Development and clinical studies of various types of representative nanocarriers for cancer therapy.
TypeNanomaterial and DrugCancer and MethodEfficacyClinical Stage and Ref.
Inorganic NPsGold and PSCRC, Breast
PTT
Effective delivery and enhances PS’ phototoxicityPreclinical [48,49]
Gold and siRNAGBM
Gene therapy
Reduced tumor-associated Bcl2 protein expressionPhase 0 [50]
Silver and Chinese herb extractsGBM
Undefined
Inhibiting blood vessel formationPreclinical [51]
Silver and longan peel powderLung ChemotherapyDown-regulated NF-κB and up-regulated Bcl2, caspase-3 and survival rate of mice.Preclinical [52]
Silica and 5-ALA, ZnPcSkin, Liver
PDT
Enhances PS’ phototoxicity, endolysosomal escapePreclinical [53,54]
Lipid NPsPhospholipid, cholesterol and
Doxil, carboplatin, paclitaxel
Kaposi’s Sarcoma, ovarian, breast
chemotherapy
Inhibit DNA synthesis and induce apoptosisPhase 1, phase 3 [55,56,57]
Phospholipid, Rg3-based liposomes and
Ceramide, PTX
HCC, breast
immunotherapy
↓ROS and M2-TAM, ↑M1-TAM and CD8+T; ↓MDSCs, TME remodelingPreclinical [58]
Polymeric NPsHPMA, PLGA, PEG-PLA, and
DOX, paclitaxel, camptotheci-n
CRC, breast, pancreatic, NSCLCs, ovarian
chemotherapy
Inhibit DNA synthesis and induce apoptosisPhase 1 to 3 [59,60,61,62]
Folate-PEG-Chems, GalNAc, PEG-b-PCL, PCL-b-PPEEA and
Daunorubici-n, siRNA
Leukemia tumor, liver, Pancreatic
Chemotherapy,
Gene therapy
Enhanced the endocytosis of cells in vitro and in vivo, hepatocyte-specific gene deliveryPreclinical [63,64,65,66]
Hybrid NPsAlbumin and
Paclitaxel
NSCLCs
Chemotherapy
Increase drug solubility, improve bioavailability, and promote absorption of drugs by cancer cellsFDA approved [67]
PEG, polyglutamic acid, mPEG and D,L-PLA and
Camptothecin, paclitaxel
NSCLCs
Chemotherapy
Increase drug solubility, improve bioavailability, and promote absorption of drugs by cancer cellsPhase 0 to 2 [68,69,70]
SPIONs, PNIPAAm-MAA and DOXLung cancer
Chemotherapy, imaging
pH-dependent manner, time-dependent mannerPreclinical [71]
Biomimetic NPsDC, tumor antigen, and sunitinibGBM, melanoma, prostate,
immunotherapy + radiochemotherapy, immunotherapy + chemotherapy
Activate T-cells’ immune responseFDA approve [72,73]
Neutrophil, RBC, Platelets and
Celastrol, tumor antigen, CpG, R848
Pancreatic cancer,
melanoma
chemotherapy, immunotherapy
Targeting tumor site, prevent liver metastasis of tumor, improve the survival rate of tumor bearing mice, activate immune responsePreclinical [14,74,75,76,77,78]
Natural NPsPlatelets and
PD-L1
Melanomas,
breast cancer,
immunotherapy
Delivery of anti-PDL1 to the surgical bed and target CTCs, reduce the risk of cancer regrowth and metastatic spreadPreclinical [79,80,81,82]
Macrophages
Chemical drugs
breast, GBM
chemotherapy
Targeted to cancer cells,
inhibit tumor invasion
Preclinical [83,84]
Exosomes mi-RNA, chemical drugs, proteinsGBM, breast, ovarian cancer
Gene therapy, chemotherapy, immunotherapy
Activate T cell response,
inhibit tumor growth
Preclinical [85,86,87,88,89]
NPs: nanoparticles; PTT: photothermal therapy; PS: photosensitizer drug; PDT: photodynamic therapy; ROS: reactive oxygen species; HCC: Hepatocellular cancer; PTX: paclitaxel; CRC: colorectal cancer; NSCLCs: non-small cell lung cancers; SPIONs: Supermagnetic iron oxide nanoparticles; PNIPAAm-MAA: radical polymerization of methacrylic acid (MAA) and N-isopropylacrylamide (NIPAAm); GBM: glioblastoma.
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Han, S.; Chi, Y.; Yang, Z.; Ma, J.; Wang, L. Tumor Microenvironment Regulation and Cancer Targeting Therapy Based on Nanoparticles. J. Funct. Biomater. 2023, 14, 136. https://doi.org/10.3390/jfb14030136

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Han S, Chi Y, Yang Z, Ma J, Wang L. Tumor Microenvironment Regulation and Cancer Targeting Therapy Based on Nanoparticles. Journal of Functional Biomaterials. 2023; 14(3):136. https://doi.org/10.3390/jfb14030136

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Han, Shulan, Yongjie Chi, Zhu Yang, Juan Ma, and Lianyan Wang. 2023. "Tumor Microenvironment Regulation and Cancer Targeting Therapy Based on Nanoparticles" Journal of Functional Biomaterials 14, no. 3: 136. https://doi.org/10.3390/jfb14030136

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