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Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 45909

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Special Issue Editor

Dr. Manuela Calin

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Guest Editor

“Medical and Pharmaceutical Bionanotechnologies” Laboratory, Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 8 B.P. Hasdeu, 050568 Bucharest, Romania
Interests: targeted drug delivery; functionalized nanoparticles; cytokines; cardiovascular diseases; inflammation; endothelium; monocytes/macrophages; natural and synthetic therapeutic agents
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Special Issue Information

Dear Colleagues,

“Smart” targeted therapies based on nanocarriers are highly attractive because, in addition to the ability to deliver the needed drugs to the specific pathological place, they have the benefit of reducing drug concentration at non-target locations ensuing in fewer side effects.

This Special Issue focuses on nanocarriers developed as efficient drug delivery systems and will include papers describing the design, preparation and characterization of various nanocarriers-based drug delivery systems with tunable composition, architecture and functionalities and their use in the treatment of inflammation associated-diseases (cardiovascular diseases, cancer, diabetes, metabolic syndrome, auto-immune diseases, neurodegenerative diseases, etc.).

Authors are invited to submit original and review articles covering all the aspects of nanocarriers developed to mediate an effective drug delivery to specific pathological locations.

Dr. Manuela Calin
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

nanoparticles
targeted delivery
surface functionalization
inflammation
cardiovascular diseases
cancer
therapeutic agents
RNA interference

Published Papers (12 papers)

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Research

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19 pages, 3422 KiB

Open AccessArticle

Enhanced Efficacy of Thiosemicarbazone Derivative-Encapsulated Fibrin Liposomes against Candidiasis in Murine Model

by Azmat Ali Khan, Amer M. Alanazi, Nawaf Alsaif, Nasser Algrain, Tanveer Ahmad Wani and Mashooq Ahmad Bhat

Pharmaceutics 2021, 13(3), 333; https://doi.org/10.3390/pharmaceutics13030333 - 4 Mar 2021

Cited by 3 | Viewed by 1692

Abstract

Candida albicans is the most studied species for the candidiasis infection and is becoming resistant towards existing antifungal drugs. Considering this, in the current study, we developed and characterized a fibrin liposome-based formulation encapsulating a novel thiosemicarbazone derivative, 2C, and evaluated its antifungal efficacy against murine candidiasis. The 2C-containing formulation was prepared by encapsulating 2C within the liposomes (2C-L) that were further encapsulated in the fibrin beads (2C-FL). The in-house synthesized 2C-FLs were spherical with a zeta potential of −34.12 ± 0.3 mV, an entrapment efficiency of 72.6 ± 4.7%, and a loading efficiency of 9.21 ± 2.3%, and they showed a slow and sustained release of 2C. Compared to free 2C, the formulation was non-toxic and exhibited serum stability, increased tissue specificity, and penetration. The 2C-FL formulation had a minimum inhibitory concentration (MIC) value of 4.92 ± 0.76 µg/mL and was able to induce apoptosis and necrosis in C. albicans in vitro. The administration of 2C-FL in C. albicans-infected mice prolonged their survival and antifungal effects when compared with the free 2C. The 2C-FL antifungal therapy significantly reduced the fungal burden and displayed an improved survival rate. In conclusion, the 2C thiosemicarbazone derivative possesses a potent antifungal activity that became more advantageous upon its encapsulation in the fibrin liposome delivery system. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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18 pages, 4906 KiB

Open AccessArticle

New Nanoparticle Formulation for Cyclosporin A: In Vitro Assessment

by Amandine Gendron, Natalie Lan Linh Tran, Julie Laloy, Romain Brusini, Aurélie Rachet, Frédéric Gobeaux, Valérie Nicolas, Pierre Chaminade, Sonia Abreu, Didier Desmaële and Mariana Varna

Pharmaceutics 2021, 13(1), 91; https://doi.org/10.3390/pharmaceutics13010091 - 12 Jan 2021

Cited by 6 | Viewed by 2878

Abstract

Cyclosporin A (CsA) is a molecule with well-known immunosuppressive properties. As it also acts on the opening of mitochondrial permeability transition pore (mPTP), CsA has been evaluated for ischemic heart diseases (IHD). However, its distribution throughout the body and its physicochemical characteristics strongly limit the use of CsA for intravenous administration. In this context, nanoparticles (NPs) have emerged as an opportunity to circumvent the above-mentioned limitations. We have developed in our laboratory an innovative nanoformulation based on the covalent bond between squalene (Sq) and cyclosporin A to avoid burst release phenomena and increase drug loading. After a thorough characterization of the bioconjugate, we proceeded with a nanoprecipitation in aqueous medium in order to obtain SqCsA NPs of well-defined size. The SqCsA NPs were further characterized using dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryoTEM), and high-performance liquid chromatography (HPLC), and their cytotoxicity was evaluated. As the goal is to employ them for IHD, we evaluated the cardioprotective capacity on two cardiac cell lines. A strong cardioprotective effect was observed on cardiomyoblasts subjected to experimental hypoxia/reoxygenation. Further research is needed in order to understand the mechanisms of action of SqCsA NPs in cells. This new formulation of CsA could pave the way for possible medical application. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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15 pages, 1989 KiB

Open AccessArticle

Redox-Responsive Nanocarrier for Controlled Release of Drugs in Inflammatory Skin Diseases

by Keerthana Rajes, Karolina A. Walker, Sabrina Hadam, Fatemeh Zabihi, Fiorenza Rancan, Annika Vogt and Rainer Haag

Pharmaceutics 2021, 13(1), 37; https://doi.org/10.3390/pharmaceutics13010037 - 29 Dec 2020

Cited by 7 | Viewed by 2648

Abstract

A synthetic route for redox-sensitive and non-sensitive core multi-shell (CMS) carriers with sizes below 20 nm and narrow molecular weight distributions was established. Cyclic voltammetric measurements were conducted characterizing the redox potentials of reduction-sensitive CMS while showcasing its reducibility through glutathione and tris(2-carboxyethyl)-phosphine as a proof of concept. Measurements of reduction-initiated release of the model dye Nile red by time-dependent fluorescence spectroscopy showed a pronounced release for the redox-sensitive CMS nanocarrier (up to 90% within 24 h) while the non-sensitive nanocarriers showed no release in PBS. Penetration experiments using ex vivo human skin showed that the redox-sensitive CMS nanocarrier could deliver higher percentages of the loaded macrocyclic dye meso-tetra (m-hydroxyphenyl) porphyrin (mTHPP) to the skin as compared to the non-sensitive CMS nanocarrier. Encapsulation experiments showed that these CMS nanocarriers can encapsulate dyes or drugs with different molecular weights and hydrophobicity. A drug content of 1 to 6 wt% was achieved for the anti-inflammatory drugs dexamethasone and rapamycin as well as fluorescent dyes such as Nile red and porphyrins. These results show that redox-initiated drug release is a promising strategy to improve the topical drug delivery of macrolide drugs. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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15 pages, 2417 KiB

Open AccessFeature PaperArticle

Mesoporous Silica Nanoparticles as a Potential Platform for Vaccine Development against Tuberculosis

by Sandra Montalvo-Quirós, María Vallet-Regí, Ainhoa Palacios, Juan Anguita, Rafael C. Prados-Rosales, Blanca González and Jose L. Luque-Garcia

Pharmaceutics 2020, 12(12), 1218; https://doi.org/10.3390/pharmaceutics12121218 - 16 Dec 2020

Cited by 14 | Viewed by 2844

Abstract

The increasing emergence of new strains of Mycobacterium tuberculosis (Mtb) highly resistant to antibiotics constitute a public health issue, since tuberculosis still constitutes the primary cause of death in the world due to bacterial infection. Mtb has been shown to produce membrane-derived extracellular vesicles (EVs) containing proteins responsible for modulating the pathological immune response after infection. These natural vesicles were considered a promising alternative to the development of novel vaccines. However, their use was compromised by the observed lack of reproducibility between preparations. In this work, with the aim of developing nanosystems mimicking the extracellular vesicles produced by Mtb, mesoporous silica nanoparticles (MSNs) have been used as nanocarriers of immunomodulatory and vesicle-associated proteins (Ag85B, LprG and LprA). These novel nanosystems have been designed and extensively characterized, demonstrating the effectiveness of the covalent anchorage of the immunomodulatory proteins to the surface of the MSNs. The immunostimulatory capacity of the designed nanosystems has been demonstrated by measuring the levels of pro- (TNF) and anti-inflammatory (IL-10) cytokines in exposed macrophages. These results open a new possibility for the development of more complex nanosystems, including additional vesicle components or even antitubercular drugs, thus allowing for the combination of immunomodulatory and bactericidal effects against Mtb. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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21 pages, 19376 KiB

Open AccessArticle

Evaluation of VCAM-1 Targeted Naringenin/Indocyanine Green-Loaded Lipid Nanoemulsions as Theranostic Nanoplatforms in Inflammation

by Elena Valeria Fuior, Cristina Ana Mocanu, Mariana Deleanu, Geanina Voicu, Maria Anghelache, Daniela Rebleanu, Maya Simionescu and Manuela Calin

Pharmaceutics 2020, 12(11), 1066; https://doi.org/10.3390/pharmaceutics12111066 - 9 Nov 2020

Cited by 15 | Viewed by 2410

Abstract

Naringenin, an anti-inflammatory citrus flavonoid, is restrained from large-scale use by its reduced water solubility and bioavailability. To overcome these limitations, naringenin was loaded into lipid nanoemulsions directed towards vascular cell adhesion molecule (VCAM)-1, exposed by activated endothelium, and delivered intravenously in a murine model of lipopolysaccharide (LPS)-induced inflammation. To follow the in vivo bio-distribution, naringenin-loaded nanoemulsions were labeled with near-infrared probe Indocyanine Green (ICG). Based on ICG fluorescence, a VCAM-1-dependent retention of nanoemulsions was detected in the heart and aorta, while ultra-high-performance liquid chromatography (UHPLC) measurements showed a target-selective accumulation of naringenin in the heart and lungs. Correlated, fluorescence and UHPLC data indicated a mixed behavior of the VCAM-1 directed nanoparticles, which were driven not only by the targeting moiety but also by passive retention. The treatment with naringenin-loaded nanoemulsions reduced the mRNA levels of some inflammatory mediators in organs harvested from mice with acute inflammation, indicative of their anti-inflammatory potential. The data support a novel theranostic nanoplatform for inflammation, the naringenin/ICG-loaded nanoparticles that either by passive accumulation or effective targeting of the activated endothelium can be employed for imaging inflamed vascular areas and efficient delivery of the encapsulated therapeutic agent. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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18 pages, 2975 KiB

Open AccessArticle

Anti-Inflammatory Polymeric Nanoparticles Based on Ketoprofen and Dexamethasone

by Eva Espinosa-Cano, Maria Rosa Aguilar, Yadileiny Portilla, Domingo F. Barber and Julio San Román

Pharmaceutics 2020, 12(8), 723; https://doi.org/10.3390/pharmaceutics12080723 - 31 Jul 2020

Cited by 14 | Viewed by 3738

Abstract

Polymeric nanoparticles that combine dexamethasone and naproxen reduce inflammation and synergistically inhibit Interleukin-12b (Il12b) transcription in macrophages. This effect can be the result of a cyclooxygenase-dependent or a cyclooxygenase-independent mechanism. The aim of this work is to obtain potent anti-inflammatory polymeric nanoparticles by the combination of dexamethasone and ketoprofen, one of the most efficient cyclooxygenase-inhibitors among non-steroidal anti-inflammatory drugs, with appropriate hydrodynamic properties to facilitate accumulation and co-release of drugs in inflamed tissue. Nanoparticles are spherical with hydrodynamic diameter (117 ± 1 nm), polydispersity (0.139 ± 0.004), and surface charge (+30 ± 1 mV), which confer them with high stability and facilitate both macrophage uptake and internalization pathways to favor their retention at the inflamed areas and lysosomal degradation and drug release, respectively. In vitro biological studies concluded that the dexamethasone-loaded ketoprofen-bearing system is non-cytotoxic and efficiently reduces lipopolysaccharide-induced nitric oxide release. The RT-qPCR analysis shows that the ketoprofen nanoparticles were able to reduce to almost basal levels the expression of tested pro-inflammatory markers and increase the gene expression of anti-inflammatory cytokines under inflammatory conditions. However, the synergistic inhibition of Il12b observed in nanoparticles that combine dexamethasone and naproxen was not observed in nanoparticles that combine dexamethasone and ketoprofen, suggesting that the synergistic trans-repression of Il12b observed in the first case was not mediated by cyclooxygenase-dependent pathways. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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12 pages, 1433 KiB

Open AccessArticle

Interaction of Lipoplex with Albumin Enhances Gene Expression in Hepatitis Mice

by Naoki Yoshikawa, Shintaro Fumoto, Keiko Yoshikawa, Die Hu, Kazuya Okami, Riku Kato, Mikiro Nakashima, Hirotaka Miyamoto and Koyo Nishida

Pharmaceutics 2020, 12(4), 341; https://doi.org/10.3390/pharmaceutics12040341 - 10 Apr 2020

Cited by 5 | Viewed by 2690

Abstract

Understanding the in vivo fate of lipoplex, which is composed of cationic liposomes and DNA, is an important issue toward gene therapy. In disease conditions, the fate of lipoplex might change compared with the normal condition. Here, we examined the contribution of interaction with serum components to in vivo transfection using lipoplex in hepatitis mice. Prior to administration, lipoplex was incubated with serum or albumin. In the liver, the interaction with albumin enhanced gene expression in hepatitis mice, while in the lung, the interaction with serum or albumin enhanced it. In normal mice, the interaction with albumin did not enhance hepatic and pulmonary gene expression. Furthermore, hepatic and pulmonary gene expression levels of albumin-interacted lipoplex were correlated with serum transaminases in hepatitis mice. The albumin interaction increased the hepatic accumulation of lipoplex and serum tumor necrosis factor-α level. We suggest that the interaction with albumin enhanced the inflammation level after the administration of lipoplex in hepatitis mice. Consequently, the enhancement of the inflammation level might enhance the gene expression level. Information obtained in the current study will be valuable toward future clinical application of the lipoplex. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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Review

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27 pages, 2521 KiB

Open AccessReview

Chronic Inflammatory Diseases, Anti-Inflammatory Agents and Their Delivery Nanosystems

by Daniela Placha and Josef Jampilek

Pharmaceutics 2021, 13(1), 64; https://doi.org/10.3390/pharmaceutics13010064 - 6 Jan 2021

Cited by 54 | Viewed by 5468

Abstract

Inflammatory diseases, whether caused by excessive stress on certain tissues/parts of the body or arising from infections accompanying autoimmune or secondary diseases, have become a problem, especially in the Western world today. Whether these are inflammations of visceral organs, joints, bones, or the like, they are always a physiological reaction of the body, which always tries to eradicate noxious agents and restore tissue homeostasis. Unfortunately, this often results in damage, often irreversible, to the affected tissues. Nevertheless, these inflammatory reactions of the body are the results of excessive stress, strain, and the generally unhealthy environment, in which the people of Western civilization live. The pathophysiology and pathobiochemistry of inflammatory/autoimmune processes are being studied in deep detail, and pharmaceutical companies are constantly developing new drugs that modulate/suppress inflammatory responses and endogenous pro-inflammatory agents. In addition to new specifically targeted drugs for a variety of pro-inflammatory agents, a strategy can be found for the use of older drugs, which are formulated into special nanodrug delivery systems with targeted distribution and often modified release. This contribution summarizes the current state of research and development of nanoformulated anti-inflammatory agents from both conventional drug classes and experimental drugs or dietary supplements used to alleviate inflammatory reactions. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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13 pages, 1002 KiB

Open AccessReview

Supramolecular and Macromolecular Matrix Nanocarriers for Drug Delivery in Inflammation-Associated Skin Diseases

by Ranime Jebbawi, Séverine Fruchon, Cédric-Olivier Turrin, Muriel Blanzat and Rémy Poupot

Pharmaceutics 2020, 12(12), 1224; https://doi.org/10.3390/pharmaceutics12121224 - 17 Dec 2020

Cited by 3 | Viewed by 3150

Abstract

Skin is our biggest organ. It interfaces our body with its environment. It is an efficient barrier to control the loss of water, the regulation of temperature, and infections by skin-resident and environmental pathogens. The barrier function of the skin is played by the stratum corneum (SC). It is a lipid barrier associating corneocytes (the terminally differentiated keratinocytes) and multilamellar lipid bilayers. This intricate association constitutes a very cohesive system, fully adapted to its role. One consequence of this efficient organization is the virtual impossibility for active pharmaceutical ingredients (API) to cross the SC to reach the inner layers of the skin after topical deposition. There are several ways to help a drug to cross the SC. Physical methods and chemical enhancers of permeation are a possibility. These are invasive and irritating methods. Vectorization of the drugs through nanocarriers is another way to circumvent the SC. This mini-review focuses on supramolecular and macromolecular matrices designed and implemented for skin permeation, excluding vesicular nanocarriers. Examples highlight the entrapment of anti-inflammatory API to treat inflammatory disorders of the skin. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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24 pages, 1365 KiB

Open AccessReview

Neutrophils and Macrophages as Targets for Development of Nanotherapeutics in Inflammatory Diseases

by Yujie Su, Jin Gao, Puneet Kaur and Zhenjia Wang

Pharmaceutics 2020, 12(12), 1222; https://doi.org/10.3390/pharmaceutics12121222 - 17 Dec 2020

Cited by 57 | Viewed by 6170

Abstract

Neutrophils and macrophages are major components of innate systems, playing central roles in inflammation responses to infections and tissue injury. If they are out of control, inflammation responses can cause the pathogenesis of a wide range of diseases, such as inflammatory disorders and autoimmune diseases. Precisely regulating the functions of neutrophils and macrophages in vivo is a potential strategy to develop immunotherapies to treat inflammatory diseases. Advances in nanotechnology have enabled us to design nanoparticles capable of targeting neutrophils or macrophages in vivo. This review discusses the current status of how nanoparticles specifically target neutrophils or macrophages and how they manipulate leukocyte functions to inhibit their activation for inflammation resolution or to restore their defense ability for pathogen clearance. Finally, we present a novel concept of hijacking leukocytes to deliver nanotherapeutics across the blood vessel barrier. This review highlights the challenges and opportunities in developing nanotherapeutics to target leukocytes for improved treatment of inflammatory diseases. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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31 pages, 1758 KiB

Open AccessReview

Nanoparticle-Based Approaches towards the Treatment of Atherosclerosis

by Artur Y. Prilepskii, Nikita S. Serov, Daniil V. Kladko and Vladimir V. Vinogradov

Pharmaceutics 2020, 12(11), 1056; https://doi.org/10.3390/pharmaceutics12111056 - 5 Nov 2020

Cited by 25 | Viewed by 4110

Abstract

Atherosclerosis, being an inflammation-associated disease, represents a considerable healthcare problem. Its origin remains poorly understood, and at the same time, it is associated with extensive morbidity and mortality worldwide due to myocardial infarctions and strokes. Unfortunately, drugs are unable to effectively prevent plaque formation. Systemic administration of pharmaceuticals for the inhibition of plaque destabilization bears the risk of adverse effects. At present, nanoscience and, in particular, nanomedicine has made significant progress in both imaging and treatment of atherosclerosis. In this review, we focus on recent advances in this area, discussing subjects such as nanocarriers-based drug targeting principles, approaches towards the treatment of atherosclerosis, utilization of theranostic agents, and future prospects of nanoformulated therapeutics against atherosclerosis and inflammatory diseases. The focus is placed on articles published since 2015 with additional attention to research completed in 2019–2020. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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18 pages, 25452 KiB

Open AccessReview

Hyaluronic Acid Nanoparticles as Nanomedicine for Treatment of Inflammatory Diseases

by N.Vijayakameswara Rao, Jun Gi Rho, Wooram Um, Pramod Kumar EK, Van Quy Nguyen, Byeong Hoon Oh, Wook Kim and Jae Hyung Park

Pharmaceutics 2020, 12(10), 931; https://doi.org/10.3390/pharmaceutics12100931 - 29 Sep 2020

Cited by 37 | Viewed by 7256

Abstract

Owing to their unique biological functions, hyaluronic acid (HA) and its derivatives have been explored extensively for biomedical applications such as tissue engineering, drug delivery, and molecular imaging. In particular, self-assembled HA nanoparticles (HA-NPs) have been used widely as target-specific and long-acting nanocarriers for the delivery of a wide range of therapeutic or diagnostic agents. Recently, it has been demonstrated that empty HA-NPs without bearing any therapeutic agent can be used therapeutically for the treatment of inflammatory diseases via modulating inflammatory responses. In this review, we aim to provide an overview of the significant achievements in this field and highlight the potential of HA-NPs for the treatment of inflammatory diseases. Full article

(This article belongs to the Special Issue Emerging Nanocarriers-Based Drug Delivery in Inflammation-Associated Diseases)

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