Search Results (5,981)

To overcome low bioavailability and high trauma in inner ear therapies, targeted delivery across the round window membrane (RWM) via hollow microneedles (HMNs) offers a promising solution. However, the fabrication of high-aspect-ratio, small-size HMNs remains challenging. This study demonstrates the successful fabrication of small-outer-diameter HMNs using a 10 μm resolution digital light processing (DLP) system. Finite element analysis (FEA) identified a double tangent-arc transition as the optimal structural design for minimizing stress concentration. To manage the heightened parameter sensitivity at sub-feature-scale fabrication, a corrected curing index (CCI) model was established via a physics-informed regression approach incorporating polymerization kinetics and nonlinear spatial intensity distribution, achieving high fitting accuracy (R² > 0.96). Under optimized parameters, the fabricated HMNs possessed mean dimensions of 805.13 μm in height, 37.54 μm in inner diameter, and 79.36 μm in outer diameter. Compressive tests exhibited a robust structural strength of up to 141 mN per needle following post-curing. Combined in silico and in vitro experiments demonstrated excellent penetration performance. Furthermore, the HMNs achieved stable, pressure-dependent delivery with volumetric flow rates rising from 0.14 mL∙min⁻¹ to 0.39 mL∙min⁻¹ as driving pressure escalated from 50 kPa to 300 kPa, validating their functional capacity for controlled drug administration. Full article

Antibody–drug conjugates (ADCs) are a pivotal technology for precision cancer therapy, harnessing the synergistic effects of antibody targeting and toxin delivery. However, traditional ADCs encounter limitations in efficacy that stem from tumor resistance, heterogeneity, and intense target competition. Dual-payload ADCs (DP-ADCs) represent a promising solution to these challenges, as they leverage dual mechanisms of action that mitigate acquired drug resistance and enhance adaptability to tumor heterogeneity. The complex structure of DP-ADCs presents substantial quality control hurdles. In this manuscript, we review the current payload selection and conjugation strategies of DP-ADCs and examine recent advances in quality control research. Specifically, we analyze the analytical challenges related to the quantification of free toxins, the determination of the total antibody content, and the characterization of the drug-to-antibody ratio and its distribution. Ultimately, the aim of this work is to provide valuable guidance for future DP-ADC quality control analyses to facilitate their clinical translation and application. Full article

Background: Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis). Drug-resistant TB remains a major public health challenge and calls for new approaches to drug development. Targeted delivery of antibacterial agents using nanoscale carriers represents one such approach. A decisive factor for efficient targeting is the judicious selection of the carrier platform. Methods: In the present study, diamond nanoparticles were evaluated as a prospective vehicle for conveying anti-TB drugs to lung cells. Conventional and analytical transmission electron microscopy were used to analyze the localization of the nanodiamonds (NDs) in the lungs of M. tuberculosis-infected mice 30 days after nanoparticle administration and 44 days post-infection. Results: The study shows that the NDs co-localize with M. tuberculosis in foamy macrophages of the lung, residing in the same cellular compartments—phagosomes/phagolysosomes and lipid droplets. These in vivo results demonstrate a high degree of macrophage-specific accumulation of NDs relative to M. tuberculosis. Conclusions: Consequently, NDs can be considered a promising carrier for targeted delivery of anti-TB therapeutics to the lungs during TB-induced inflammation. Full article

This study examines non-Newtonian electromagnetohydrodynamic (EMHD) blood flow via a diseased curved artery with minor stenosis and an aneurysm, adding a no-slip boundary condition, using targeted medication delivery of nanoparticles. The non-Newtonian behavior of blood flow is accounted for by the Casson fluid model. Using Corcione’s model, we have calculated the effective viscosity and thermal conductivity of nanofluids. The interaction of the nanofluid with physical phenomena such as viscous dissipation, electro-osmosis, radially applied uniform magnetic field and Joule heating can change the hemodynamic parameters of the fluid. The Crank–Nicolson approach has been used to calculate the velocity, temperature, and concentration patterns within the Debye–Huckel linearization approximation. Streamlines are delineated to analyze flow patterns across distinct physical factors. This study supports the design of magnetically guided $F{e}_3{O}_4$ nanoparticle–based targeted drug delivery systems for treating vascular diseases such as stenosis and aneurysm, improving site-specific therapeutic efficiency. The numerical insights into thermal effects and arterial geometry help to optimize nanoparticle transport, enhancing treatment precision while minimizing systemic side effects. Full article

Pulmonary fibrosis (PF) is a progressive and often fatal interstitial lung disease for which the currently available pharmacological therapies remain largely limited to slowing disease progression rather than reversing established fibrosis. This limitation has stimulated increasing interest in innovative therapeutic platforms capable of modulating complex fibrotic pathways. In this context, exosomes—nanoscale extracellular vesicles—have emerged as promising cell-free nanocarriers due to their intrinsic biocompatibility, low immunogenicity, and ability to be engineered for targeted drug delivery. In this review, we provide a comprehensive overview of both natural and engineered exosome-based strategies for the diagnosis and treatment of pulmonary fibrosis. We summarize recent advances in exosome engineering, including ligand functionalization, glycoengineering, and therapeutic cargo loading, highlighting how these approaches may support the development of more targeted and potentially personalized nanotherapeutic strategies. We further discuss emerging hybrid delivery platforms, such as exosome–liposome chimeras and hydrogel-based depots, which may enhance pulmonary retention, improve therapeutic durability, and enable controlled drug release. Finally, we outline key challenges and opportunities for clinical translation, including large-scale manufacturing, regulatory considerations, and clinically relevant delivery routes such as inhalation-based administration. Collectively, this review provides a translational perspective on engineered exosomes as emerging nanotherapeutic platforms for pulmonary fibrosis. Full article

Macrophage-derived extracellular vesicles (EVs) have emerged as promising biomimetic platforms for targeted cancer drug delivery due to their biocompatibility, immune-modulatory properties, and tumor-homing capabilities. Among macrophage subtypes, M1-polarized macrophages exhibit potent anti-tumor functions characterized by pro-inflammatory cytokine secretion, improved antigen presentation, and the ability to remodel the tumor microenvironment (TME). Utilizing these properties, M1-polarized macrophage-derived EVs serve as cell-free therapeutic systems capable of delivering bioactive cargo while simultaneously promoting anti-tumor immune responses. However, the clinical application of natural EVs is limited by low yield, heterogeneity, and challenges in large-scale production. Artificial nanovesicles (ANVs) have been developed to address these limitations, offering improved scalability, compositional control, and reproducibility. This review provides an overview of macrophage differentiation and polarization, with a focus on the immunological profile and anti-tumor mechanisms of M1-polarized macrophages. It further discusses current methodologies for EV isolation and ANV generation, along with cargo loading strategies that balance encapsulation efficiency and vesicle stability. In addition, this review also emphasizes their targeting approaches, cellular uptake pathways, and the intracellular trafficking mechanisms that influence delivery efficiency and therapeutic outcomes. Key challenges, including standardization, biological barriers, and functional consistency, are critically evaluated. Emerging strategies that integrate vesicle engineering with personalized medicine underscore the potential of these systems to advance precision oncology. Full article

Objective: Self-assembled nanoparticles (SANs) naturally occurring in Traditional Chinese Medicine (TCM) decoctions are promising drug carriers due to their biocompatibility, but uncontrolled assembly often leads to poor stability, limiting transdermal permeability and industrial application. This study aimed to fabricate stable and uniform SANs from licorice by precisely regulating the controlled nanoprecipitation of its water- and alcohol-extracted components. The transdermal delivery efficiency and therapeutic efficacy of the SANs in the treatment of atopic dermatitis (AD) were evaluated. Methods: Licorice self-assembled nanoparticles (LD-SANs) were prepared by mixing water and ethanol extracts of licorice, followed by ethanol evaporation under reduced pressure to trigger nanoprecipitation. In vitro transdermal tests compared the delivery efficiency of six major bioactive compounds between LD-SANs and traditional licorice decoction (LD). The penetration mechanism was investigated via passive diffusion and cellular uptake studies. In an AD mouse model, the therapeutic effects and expression of tight junction (TJ) proteins (Occludin and Claudin-1) were assessed. Results: The average particle size of LD-SANs is 200 nm, and it is uniform and stable. LD-SANs significantly enhanced the delivery efficiency of all six bioactive compounds compared to LD. Mechanistic studies revealed a unique “dual-channel” penetration mechanism: the nanoscale size enabled passive diffusion through hair follicles, intercorneocyte lipid gaps, and skin appendages, while perifollicular antigen-presenting cells (APCs) actively recognized and internalized the nanoparticles, creating a cell-mediated active targeting route that collectively boosted skin accumulation. In the AD model, LD-SANs promoted the expression of Occludin and Claudin-1 in the epidermal granular layer, reinforcing intercellular barrier integrity. Conclusions: By combining “efficient penetration” and “barrier repair”, LD-SANs demonstrated notable therapeutic efficacy in AD. This work transforms a traditional decoction into a well-characterized, high-performance nanomedicine and offers a novel strategy for developing TCM-based transdermal delivery systems. Full article

Plant-derived extracellular vesicles (PDEVs) are a novel category of natural nanocarriers with widespread availability, low immunogenicity, high biocompatibility, and inherent pharmacological activity. These features underscore their value as dual-function systems capable of serving as both carriers and bioactive agents. Unlike previous reviews that focused primarily on disease-specific applications or on individual engineering techniques, this review established a conceptual framework integrating three interconnected dimensions: (i) engineering strategies that address the inherent limitations of PDEVs (targeting, stability, loading efficiency); (ii) the carrier-performance-synergy paradigm linking PDEV composition to therapeutic outcomes; and (iii) gel-composite design principles that transform local retention into a controllable delivery platform. This review delves into various engineering methodologies, including targeted modification, enhanced stability, and optimized drug loading, while elucidating the performance characteristics of PDEVs as drug carriers, focusing on their protective, targeting, and controlled-release properties. It notably investigates the synergistic interactions between the intrinsic bioactivity of PDEVs and the drugs they deliver. Furthermore, this review highlights advanced applications of PDEV gel composites in localized drug delivery, specifically emphasizing their clinical potential for treating dermatological conditions. Finally, it highlights the current challenges faced by PDEVs and anticipates future research directions, such as synthetic biology, multi-omics analysis, and clinical translation. This review provides a theoretical framework for the rational design and clinical translation of PDEVs. It thereby promotes their innovative development in precision nanomedicine Full article

Fatty acids (FAs) have drawn attention in the field of oncology due to their multifaceted role, not only as structural components of lipid-based delivery systems but also as functional moieties that can enhance the pharmacokinetic and biological behavior of anticancer drugs and, subsequently, their therapeutic performance. Due to their biocompatibility, structural diversity, high affinity for biological membranes, and albumin-binding capacity, FAs can increase drug lipophilicity, membrane permeability, systemic distribution, tissue distribution, and enable controlled enzymatic release. All these properties endorse the development of nanocarriers containing FAs, such as liposomes, lipid nanoparticles (LNPs), self-nanoemulsifying drug delivery systems (SNEDDS), and self-assembling lipidic prodrugs (LAPs). In addition, several FAs, especially polyunsaturated FAs, seem to have a direct anticancer activity by modulating lipid metabolism, oxidative stress, membrane organization, and regulating cell death pathways. This review summarizes the FA conjugation chemistry, the influence of FA on the pharmacokinetics and tumor-targeting capacity of anticancer agents, and the current developments in FA-based cancer treatment strategies, while also covering the biological functions of FA in cell death pathways and cancer metabolism. By integrating medicinal chemistry, nanocarrier design, pharmacokinetic modulation, and tumor lipid biology, this review positions FA-based strategies as a relevant and evolving platform for improving anticancer drug delivery, tumor selectivity, and therapeutic performance. Full article

Background: Glioblastoma (GBM) remains a lethal malignancy due to temozolomide (TMZ) resistance and limited drug penetration across the blood–brain barrier, largely driven by hyperactive DNA damage repair mechanisms such as poly (ADP-ribose) polymerase (PARP). To address these challenges, we developed folic acid-targeted PLGA–zein hybrid core–shell nanoparticles for the codelivery of the alkylating agent TMZ and the natural PARP inhibitor Ellagic acid (FA-TMZ/EA-PZ-CS NPs), thereby enabling simultaneous enhancement of drug delivery and suppression of chemoresistance pathways. Methods and Results: The dual-drug nanoplatform was fabricated using a double-emulsion solvent evaporation method and functionalized via EDC/NHS-mediated folic acid conjugation to promote receptor-mediated uptake. Physicochemical characterisation confirmed uniform spherical morphology, high colloidal stability, efficient drug encapsulation, and sustained biphasic drug release consistent with a core–shell diffusion mechanism. In LN229 glioblastoma cells, folic acid conjugation significantly enhanced cellular internalisation and cytotoxic efficacy compared to free drugs and non-targeted nanoparticles. Combination index analysis revealed strong synergism between TMZ and ellagic acid, resulting in markedly reduced IC₅₀ values. Mechanistic studies demonstrated apoptosis induction, increased DNA damage, inhibition of cell migration at sub-cytotoxic concentrations, and downregulation of PARP gene expression. Conclusion: Overall, this study establishes a targeted core–shell nanotherapeutic strategy that integrates chemotherapy with DNA repair inhibition to overcome TMZ resistance, offering a mechanistically sound strategy that serves as a foundational framework for future translational research. Full article

Resistance to systemic therapy remains the defining challenge in the management of gastric cancer (GC) and esophageal adenocarcinoma (EAC). While genomic drivers of resistance are well characterized, traditional bulk profiling has failed to capture the physical rules governing tumor survival within the complex tissue ecosystem. Emerging data from 2024–2025, leveraging high-resolution spatial transcriptomics and multi-omics, have recontextualized resistance as a phenomenon of “spatial privilege” rather than solely an intrinsic cellular fate. This review summarizes recent evidence to define “architectural refuges”: distinct spatial niches that physically shield malignant clones from cytotoxic and targeted agents. We delineate three critical resistance domains common to upper gastrointestinal adenocarcinomas: (1) The “Excluded” Niche, where specific cancer-associated fibroblast (CAF) subpopulations (iCAFs vs. myCAFs) and stiffened extracellular matrix create hypovascular zones that limit drug delivery; (2) the “Immune-Tolerant” Niche, characterized by the spatial exclusion of CD8+ T cells and the recruitment of suppressive myeloid populations via the MIF/CD74 and USP14 axes; and (3) the “Metabolic” Niche, where mitochondrial heterogeneity and lipid metabolic symbiosis establish nutrient-deprived niches that select for stem-like, dormant states. By mapping these conserved spatial determinants from primary GEJ tumors to peritoneal and distant metastases, we argue that overcoming resistance requires an advancement: moving beyond targeting individual mutations to dismantling the multicellular architecture that sustains malignancy. Full article

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a significant pathogen for both hospital-acquired and community-acquired infections, characterized by its strong epidemic potential and high mortality rate, posing a severe threat to global public health. CRKP spreads widely across the globe through the horizontal transfer of plasmid-mediated resistance genes such as *blaKPC*, *blaNDM*, and *blaOXA-48*. The clinical treatment options for this bacterium are limited, and its resistance has been increasing year by year, urgently necessitating the development of new antimicrobial drugs or alternative strategies. In recent years, the CRISPR-Cas system has shown great potential in the diagnosis and treatment of CRKP, including rapid detection and identification, gene editing, antimicrobial strategies, and resistance inhibition. For instance, CRISPR-Cas12a/13a can be used for the rapid detection and identification of CRKP, while CRISPR-Cas9/Cas3 can target resistance genes to reverse the resistance of strains. With the advancement of delivery and biotechnologies, the CRISPR-Cas system is expected to become an important tool against drug-resistant CRKP. This review focuses on the application of the CRISPR-Cas system in the detection and treatment of CRKP, analyzing its technical advantages, limitations, and future development directions. Full article

Autoimmune diseases are characterized by chronic inflammation, immune dysregulation, and excessive oxidative stress, which collectively contribute to a progressive tissue damage and organ dysfunction. Although conventional immunosuppressive and anti-inflammatory therapies remain the main therapeutic approach, their clinical efficacy is often limited by poor pharmacokinetic properties, low tissue selectivity, systemic toxicity, and adverse effects following long-term administration. In this context, antioxidant-based nanoformulations have emerged as promising multi-target therapeutic strategies for the modulation of oxidative and inflammatory pathways involved in autoimmune disorders. This review focuses on polymeric and non-polymeric nanoformulations designed to improve the solubility, stability, bioavailability, controlled release, and targeted delivery of antioxidant and anti-inflammatory agents for autoimmune disease treatment. Recent advances in nanocarrier systems applications, including nanogels, poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), polymethacrylate, chitosan, hyaluronic acid, hydroxyapatite (HAP), lipid-based and ROS-responsive nanosystems, are discussed. The therapeutic potential of nanoencapsulated steroidal and non-steroidal anti-inflammatory drugs, antioxidant compounds, enzymes, inorganic elements, and nucleic acid-binding systems is evaluated through preclinical and limited clinical evidence. Many of these reported nanoformulations exhibit enhanced therapeutic efficacy, improved tissue targeting, reduced systemic toxicity, and the ability to simultaneously modulate oxidative stress and inflammatory signaling pathways. Despite the encouraging findings, important challenges remain regarding clinical translation, long-term safety, reproducibility, and large-scale production. In overall, antioxidant nanoformulations represent a promising and evolving platform for the development of more effective and targeted therapies against autoimmune diseases. Full article

Cryptococcosis, caused by Cryptococcus neoformans, remains a major cause of mortality in immunocompromised patients, with treatment increasingly limited by resistance and toxicity associated with Amphotericin B (Amp B). In this study, methylglyoxal (MG) was evaluated as a virulence-targeted antifungal strategy, with emphasis on its liposomal delivery. MG exhibited superior antifungal activity as compared to Amp B, demonstrating lower MIC values and significantly enhanced inhibition of biofilm formation and laccase activity, key determinants of cryptococcal pathogenicity. Notably, MG showed potent intracellular antifungal activity within macrophages, where C. neoformans persists. Liposomal MG (Lip-MG) markedly reduced macrophage-associated fungal burden under the tested conditions, markedly outperforming both free MG and Amp B formulations. In a leukopenic mouse model of systemic infection, liposomal MG significantly improved survival (up to ~70%) and reduced pulmonary fungal burden as compared to Amp B, which showed limited therapeutic benefit. Importantly, MG-based formulations exhibited a favorable safety profile, with significantly lower nephrotoxicity than Amp B. Collectively, these findings demonstrate that Lip-MG acts through a dual virulence-targeted activity mechanism while effectively eliminating intracellular infection. This dual action, combined with improved safety, highlights MG-based nanotherapy as a promising and translational alternative for the treatment of drug-resistant cryptococcosis. Full article

Breast cancer remains a leading cause of cancer-related mortality worldwide, with treatment resistance, recurrence, and metastasis significantly limiting the effectiveness of conventional therapies. Photodynamic therapy (PDT) has emerged as a minimally invasive and highly selective approach, utilizing photosensitizer-generated reactive oxygen species (ROS) to achieve precise tumor cytotoxicity while preserving surrounding healthy tissue. However, clinical translation of PDT remains constrained by critical biological barriers within the tumor microenvironment, including tumor hypoxia, limited light penetration, poor photosensitizer stability, and inefficient cellular uptake. Antigen-targeted liposomal nanocarriers offer a compelling solution by enabling targeted drug delivery and tumor-specific photosensitizer accumulation, prolonged systemic circulation, and enhanced cellular internalization. Their multifunctional architecture uniquely supports combinational therapeutic strategies, integrating PDT with chemotherapy, photothermal therapy, gene therapy, X-ray-induced photodynamic therapy (X-PDT) and immune checkpoint blockade, thereby amplifying antitumor efficacy and overcoming drug resistance mechanisms. This review comprehensively summarizes recent advances in liposome-based PDT for breast cancer, highlighting multimodal therapeutic integration. Special emphasis is placed on preclinical and emerging clinical outcomes, pilot-scale manufacturing considerations, and strategies to minimize immune clearance. Full article