ABSTRACT Proteolysis‐targeting chimeras (PROTACs) are promising therapeutic agents for targeted protein degradation via the ubiquitin‐proteasome system; however, their clinical application is severely constrained by poor membrane permeability due to high molecular weight and polar surface area, limiting passive diffusion. Emerging evidence suggests that receptor‐mediated endocytosis within tumor microenvironments provides an alternative and potentially generalizable entry route for PROTAC delivery independent of classical diffusion. This review proposes a systematic framework for tumor endocytosis‐guided PROTAC delivery, centered on the identification and exploitation of endocytic biomarkers. A three‐tiered screening strategy is established based on tumor‐selective expression, validated internalization capacity, and functional relevance to tumor dependency. Using this framework, nine representative biomarkers are evaluated with respect to endocytic pathways, intracellular trafficking fate, and delivery suitability. Furthermore, we present a unified PROTAC engineering strategy matrix integrating ligand design, cleavable linker chemistry, and endosomal escape modules to align with receptor‐specific trafficking behaviors. A multiscale validation pipeline covering binding, internalization, intracellular release, and in vivo pharmacodynamics is also outlined. Collectively, this review establishes tumor endocytic pathways as programmable delivery interfaces, providing a rational roadmap for next‐generation PROTAC design with improved efficiency and translational potential.
ABSTRACT Uncontrolled bleeding in wet or actively hemorrhaging environments remains a major clinical challenge in trauma management and surgical procedures. Conventional hemostatic agents and tissue adhesives often exhibit insufficient adhesion strength and delayed coagulation upon contact with blood or moisture at the tissue interface. Inspired by the underwater adhesion mechanism of barnacle cement, we developed an injectable, multifunctional hemostatic adhesive that achieves rapid coagulation, strong adhesion to wet tissues, and inherent antibacterial properties. The adhesive integrates a silicone oil‐assisted water‐displacement phase with a bioadhesive polymer network composed of carboxymethyl chitosan, hyaluronic acid, and quaternized chitosan. In vitro tests revealed a markedly reduced blood clotting index (9.0% ± 0.6%) and shorter clotting time (2.6 ± 0.5 min), surpassing the performance of commercial gelatin sponges. Enhanced red blood cell adsorption and superior wet tissue adhesion strength (27.3 kPa on porcine skin) compared to fibrin glue further confirm its hemostatic efficacy. The adhesive also demonstrated excellent cytocompatibility and significant antibacterial activity. Overall, this barnacle‐inspired injectable adhesive offers a promising approach for achieving rapid hemostasis and infection‐resistant wound sealing in moist clinical settings.
ABSTRACT Artificial intelligence (AI) and gene editing are increasingly being applied to the design and evaluation of mRNA therapeutics. Although mRNA‐based medicines have achieved clear clinical impact in vaccination, broader applications remain limited by mRNA instability, delivery barriers, tissue selectivity, and unwanted immunogenicity. This review examines how AI and gene editing can be combined to address these constraints. AI‐based models support predictive optimization of untranslated regions, codon usage, secondary structure, and lipid nanoparticle (LNP) formulations, thereby improving the efficiency of sequence and delivery‐system design. In parallel, CRISPR‐Cas (clustered regularly interspaced short palindromic repeats‐associated proteins) systems, base editors, and emerging RNA‐editing tools provide platforms for disease modeling, target validation, and functional testing of mRNA‐based interventions. We emphasize that the value of this convergence lies in iterative workflows: gene‐editing screens generate quantitative datasets for model training, whereas AI helps prioritize editing strategies, guide sequence refinement, and improve delivery design. We also summarize representative applications, translational limitations, and prospects for closed‐loop AI‐gene editing platforms. Overall, the integration of computational prediction with programmable genome and RNA engineering may support more precise, adaptable, and clinically translatable mRNA therapeutics.
ABSTRACT Diabetes mellitus (DM), a multifactorial metabolic condition characterized by persistent hyperglycemia, causes serious systemic complications. Although conventional treatment modalities are widely used, their effectiveness in diabetes management is often limited by side effects and insufficient targeting of underlying pathological processes. This review examines the in vivo mechanisms, therapeutic potential, and future perspectives of silver nanoparticles (AgNPs) in diabetes management. Biogenic AgNPs, particularly those synthesized using plant or microbial systems, have gained increasing interest due to their improved biocompatibility and multifunctional biological properties. In vivo studies indicate that these nanomaterials regulate glycemic levels, preserve pancreatic cell integrity, modulate lipid metabolism, and attenuate inflammation and oxidative stress through signaling pathways involving reactive oxygen species (ROS), nuclear factor kappa B (NF‐B), and phosphoinositide 3‐kinase/protein kinase B (PI3K/Akt). Additionally, these nanosystems can function as carriers for targeted drug delivery, potentially enhancing therapeutic outcomes. However, differences in synthesis methods, properties, and study results make it difficult to compare them. Moreover, insufficient results regarding safety and efficacy have been reported for these nanoparticles. However, several challenges have to be addressed for the safe and effective use of these nanoparticles in diabetes management.
ABSTRACT Tubular tissues, including the trachea, pulmonary artery, and coronary artery, possess the complex branched geometries crucial for physiological functions. This study presents a rigorous quantitative framework for evaluating the geometric accuracy of 3D‐printed tubular models. By leveraging high‐resolution CT imaging and computational reconstruction, the framework provides a high‐fidelity basis for simulating coronary blood flow. Utilizing Mimics and 3‐matic software, anatomical structures were converted into 3D STL files. Accuracy was assessed by comparing these files to the original DICOM images and subsequently comparing 3D‐printed physical models back to the digital STL counterparts via multi‐axial measurements at identical anatomical landmarks along the X , Y , and Z axes. Statistical validation, including linear regression, Pearson's correlation, ICC, and Bland–Altman plots, revealed the excellent geometric fidelity ( r ² > 0.99, ICC = 0.98) with negligible localized deformations. Furthermore, we integrated coronary blood flow‐perfusion simulation under the normal and diseased conditions to demonstrate the potential of the reconstructed model as a non‐invasive tool for diagnosis and treatment planning. These findings validate the precision and reliability of high‐fidelity 3D‐printed tubular as reliable tools for preoperative planning, personalized surgical simulation, and advanced medical education. Also, this study provided a robust platform for improving clinical outcomes in complex branched tissue interventions.
ABSTRACT Poly(disulfide)s represent a class of dynamic polymers whose synthesis is facilitated by the reversible exchange and recombination of disulfide bonds. This unique polymerization mechanism, combined with the structural flexibility of cyclic disulfide monomers and the diversity of ring‐opening polymerization (ROP) methods, enables precise control over polymer architecture and functionality. The resulting materials exhibit remarkable characteristics including reversible redox‐responsiveness, tunable degradation kinetics, self‐healing capabilities, and enhanced cellular uptake efficiency. This review systematically examines the fundamental aspects of poly(disulfide)s, beginning with the design principles of monomer structures and progressing through various ROP strategies such as thermal, photo‐initiated, and catalyst‐mediated approaches. We critically analyze how these synthetic parameters influence key polymer properties including molecular weight distribution, stimulus responsiveness, and biocompatibility. The application potential of poly(disulfide)s in drug delivery is comprehensively explored, with particular focus on their performance in nucleic acid delivery systems for gene therapy, protein and peptide delivery for biotherapeutic applications, and small molecule drug carriers for enhanced therapeutic efficacy. By integrating recent advances in polymer chemistry with biomedical engineering perspectives, this review aims to provide valuable insights for the rational design of poly(disulfide)‐based delivery platforms and their translation into clinical applications.
ABSTRACT To identify effective drugs for breast cancer treatment, it is essential to establish physiologically relevant models. Traditional models based on 2D cultures or 3D scaffold‐free spheroids lack the crucial cell–extracellular matrix (ECM) interactions, known to significantly impact drug sensitivity. A newly developed 3D culture format using a network of the recombinant spider silk protein FN‐silk has demonstrated ECM‐like interactions and maintenance of subtype‐specific marker expression in breast cancer cells. In the current study, chemotherapy drug treatment experiments were conducted on the breast cancer cell lines MCF‐7, MDA‐MB‐231, and SK‐BR‐3 cultured in 2D, spheroids, and FN‐silk networks. The results suggest that FN‐silk networks hold promise as a base for an in vitro 3D model assessing the effects of chemotherapeutic agents. Comparing drug responses revealed that cells cultured in FN‐silk networks were generally less sensitive to the drugs tested—as compared to 2D cultures—suggesting that FN‐silk‐supported 3D culture could have higher clinical relevance. Moreover, the results showed improved reproducibility with FN‐silk networks compared to spheroids. This study concludes that FN‐silk networks have the potential to support the establishment of a valuable 3D tumor model for the development of personalized breast cancer treatments and thereby contribute to improved success rates in drug development.
ABSTRACT Glaucoma is a chronic optic neuropathy characterized by progressive retinal ganglion cell (RGC) loss and visual field deterioration, with elevated intraocular pressure (IOP) representing the primary modifiable risk factor. Conventional topical pharmacotherapy, while effective in lowering IOP, suffers from poor ocular bioavailability (< 5%), frequent dosing requirements, and suboptimal patient adherence. Here we review the evolution of ocular drug delivery systems for glaucoma management, encompassing both clinically available platforms and emerging nanotechnological approaches. Clinically deployed modalities—including medicated contact lenses, ocular inserts, punctal plugs, and surgical implants—have advanced from simple sustained‐release devices to sophisticated platforms capable of targeted, prolonged drug delivery to the anterior segment. Concurrently, novel systems based on nanoparticles, dendrimers, liposomes, hydrogels, and stimuli‐responsive materials are being developed to overcome ocular barriers, enhance corneal penetration, and enable spatiotemporally controlled drug release. These innovations promise to transform glaucoma therapy by reducing dosing frequency, minimizing systemic side effects, and improving long‐term patient compliance. However, clinical translation faces formidable challenges, including manufacturing scalability, sterilization stability, and rigorous safety validation. This review provides a comprehensive framework for understanding current and future drug delivery strategies, highlighting how biomaterial engineering and nanomedicine are reshaping the therapeutic landscape for this chronic, sight‐threatening disease.
ABSTRACT Polyvinyl alcohol (PVA) hydrogels have adjustable mechanical properties and good biocompatibility, with broad prospects in heart valve replacement. Constructing PVA hydrogels with biomimetic structure and anisotropic mechanical properties has become a research hotspot due to the directional collagen layer of heart valves. In this study, agarose (AG) is utilized not only as a reinforcing agent but also as a modifier to enable the formation of a biomimetic, fiber‐oriented hydrogel film. By exploiting the temperature‑dependent crosslinking of AG, we fabricate a hydrogel film via shear force induction, with a well‑aligned fibrous microstructure (mean fiber diameter 0.16 ± 0.03 μm). Mechanical evaluations reveal that the oriented hydrogel film gelled at 60°C achieves optimal performance, with tensile tangent modulus values ranging from 0.31 to 4.01 MPa perpendicular to the fiber direction and 0.33–6.05 MPa parallel to the fibers. Corresponding tensile strengths reach 1.75 and 2.63 MPa, respectively, satisfying the mechanical demands of pulmonary valve tissue. Furthermore, in vitro assays demonstrate excellent cytocompatibility (cell viability > 92%) and hemocompatibility (hemolysis rate < 2%). These findings highlight that the oriented PVA‑AG hydrogel film, combining anisotropic mechanics and biocompatibility, is a promising biomimetic material for artificial heart valves.
ABSTRACT Hydrogels have emerged as promising candidates for infected wound repair owing to their injectability and in situ gelation properties. In this study, an injectable, in situ forming hydrogel, PGBP, was designed and fabricated based on polyglutamic acid (PGA), and its efficacy in accelerating infected wound healing was evaluated. The PGB polymer was synthesized via amidation of PGA with N‐methacryloyl‐1,6‐hexanediamine (MHB), followed by crosslinking with 4‐arm‐PEG‐SH through Michael addition to form PGBP. The resulting hydrogel exhibited a porous three‐dimensional network, high swelling capacity and water retention, excellent blood compatibility, and suitable mechanical properties for wound coverage. When loaded with amikacin (Ami), the Ami@PGBP hydrogel demonstrated potent in vitro antibacterial activity against Escherichia coli and Staphylococcus aureus , along with a sustained drug release profile. Moreover, PGBP significantly enhanced the cellular antioxidant capacity of RAW 264.7 cells, scavenged free radicals (DPPH, ABTS, and •OH), reduced the expression of pro‐inflammatory cytokines (IL‐1β, IL‐6, TNF‐α), and promoted the migration of co‐cultured RAW264.7 and C166 cells. In a murine full‐thickness infected wound model, Ami@PGBP treatment accelerated wound closure, promoted re‐epithelialization and collagen deposition, facilitated skin appendage regeneration, and markedly downregulated both local and systemic inflammatory markers. In vivo biosafety assessments confirmed the hydrogel's biocompatibility and complete biodegradation within 15 days, with no observed adverse effects. Therefore, Ami@PGBP exhibits considerable potential as a multifunctional, safe, and effective dressing for the management of infected wounds.
ABSTRACT Herbal extracts often demonstrate promising in vitro activity but limited in vivo efficacy due to poor solubility, permeability, and stability. Phytosomal delivery systems offer a strategy to increase the transdermal delivery and bioavailability. This study aimed to develop and optimize a Leucas aspera phytosomal thermogel for improved topical treatment of psoriasis. Phytosomes were‐prepared from phospholipid complexes and optimized via a Box–Behnken design. The optimized formulation was evaluated for vesicle size, zeta potential, entrapment efficiency (EE), in vitro drug release, and skin deposition. Anti‐psoriatic efficacy was assessed in an imiquimod induced psoriasis mouse model through PASI scoring, ear thickness measurement, organ index analysis, transepidermal water loss and hydration studies, and histopathology. The optimized PHY gel exhibited a particle size of 92.23 ± 9.1 nm, zeta potential of −32.45 ± 0.43 mV, EE of 89.1 ± 4.6%, and cumulative drug release of 94.5 ± 1.3%. Skin deposition was significantly greater (82.61 ± 1.86%) than that of the unmodified extract gel. In vivo, the phytosome gel reduced imiquimod induced psoriasis severity, demonstrating efficacy comparable to that of the reference formulation. Overall, the Leucas aspera phytosome gel significantly improved dermal delivery and therapeutic efficacy, highlighting phytosomal systems as a promising platform for topical psoriasis therapy.
ABSTRACT Liposomal nanocarriers are clinically established platforms for targeted drug delivery due to their biocompatibility and ability to encapsulate both hydrophilic and hydrophobic agents. However, conventional single‐drug liposomes are limited by suboptimal efficacy, systemic toxicity, and multidrug resistance. Dual‐drug‐loaded liposomes (DDLs) address these limitations by enabling co‐delivery of synergistic agents within a single nanocarrier. This review provides an integrated analysis of DDL systems, focusing on formulation design, drug loading strategies, and key physicochemical parameters governing encapsulation efficiency and controlled release. Mechanistic insights into therapeutic enhancement are highlighted, including modulation of efflux transporters, reversal of epithelial–mesenchymal transition, and synchronized intracellular delivery. The impact of ligand‐mediated functionalization on tumor targeting and cellular uptake is also critically evaluated. Unlike existing reviews, this work provides a unified framework integrating formulation design, mechanistic insights into drug synergy, and translational challenges specific to DDLs, addressing a critical gap in the existing literature. Preclinical and clinical evidence, including approved formulations such as Vyxeos, is discussed. Remaining barriers include scale‐up, reproducibility, immune interactions, and regulatory complexity. Future directions emphasize personalized and stimulus‐responsive nanomedicine for improved cancer therapy.
ABSTRACT Chronic wounds pose a major clinical challenge due to a complex pathophysiological condition. It is characterized by persistent inflammation, excessive oxidative stress, and a high risk of bacterial infection, which hinders tissue repair. To address this, a multifunctional hydrogel dressing based on gallic acid conjugated chitosan (G‐CHI) and integrated with simvastatin and heparin‐functionalized Ag/Zn‐doped bioactive glass (HBG). The incorporation of gallic acid improved the structural integrity and viscoelastic behavior of the hydrogel. The release kinetics study demonstrated controlled liberation of Ag + and Zn 2+ ions within biologically safe limits over 24 h, while simvastatin exhibited diffusion‐controlled release behavior. The hydrogel also exhibited desirable adhesive properties, indicating its suitability as a wound dressing material. In vitro biofunctional assays showed enhanced antioxidant activity (~75% free radical scavenging), hemocompatibility (< 5% hemolysis), and effectiveness against both Staphylococcus aureus and Escherichia coli (> 90% efficacy in time kill assay). Further, synergistic release of simvastatin and bioglass showed enhanced proliferation of fibroblast (NIH 3T3), keratinocyte (HaCaT), and endothelial cells (SVEC), accompanied by increased collagen deposition compared to control groups. These findings suggest that the synthesized hydrogel (BSG‐CHI) provides a favorable microenvironment for tissue regeneration and wound management applications.
Vascular calcification is highly associated with cardiovascular morbidity and mortality among patients with chronic kidney disease (CKD). Despite its clinical severity, no effective therapies exist to halt its progression. Sirtuin 6 (SIRT6) has recently emerged as a promising therapeutic target for vascular calcification. Our prior work demonstrated that SIRT6 activation inhibits vascular calcification by attenuating the osteogenic trans differentiation of vascular smooth muscle cells (VSMCs). While the natural compound cyanidin can activate SIRT6, its clinical translation is hampered by poor bioavailability and the absence of targeted delivery systems. To address this, we developed a dual targeting nanoplatform (TROC) based on Ti₃C₂ nanosheets co‐assembled with osteocalcin (OCN) and RANKL antibodies for the targeted delivery of cyanidin. Leveraging data from the Framingham Heart Study offspring cohort and in vitro VSMC models, we first established dietary anthocyanins as an independent protective factor against aortic calcification. We then demonstrated that TROC exhibits excellent stability and dose‐dependently reduces calcium deposition in VSMCs. Furthermore, in vivo fluorescence and computed tomography (CT) multimodal imaging confirmed the selective accumulation of TROC at calcification sites and its efficacy in alleviating vascular calcification. This novel drug delivery system represents a promising strategy for advancing the clinical treatment of Vascular calcification.
The intratumoral microbiome has emerged as a critical component of the tumor microenvironment (TME), playing a significant role in tumorigenesis, pathological classification, metastasis, and prognosis. The nutrient-rich, hypoxic, acidic, and immunosuppressive nature of the TME facilitates the establishment of diverse intratumoral microbiome communities. In turn, the intratumoral microbiome further contributes to the formation of cold TME through mechanisms such as genetic and epigenetic alterations, pro-inflammatory responses, immune modulation, tumor metastasis, and enhanced drug resistance. Targeting and eliminating the intratumoral microbiome using nanotechnology presents a unique therapeutic strategy for overcoming chemotherapy resistance and improving the immunosuppressive TME. This review summarizes the microbial characteristics of various tumors and microbiome-mediated oncogenic mechanisms, with particular emphasis on recent advancements in nanotechnology aimed at eliminating the intratumoral microbiome and reprogramming the cold TME, thereby enhancing the efficacy of tumor immunotherapy. Our aim is to provide valuable insights to strengthen the effectiveness of tumor immunotherapy.
Vascular calcification is highly associated with cardiovascular morbidity and mortality among patients with chronic kidney disease (CKD). Despite its clinical severity, no effective therapies exist to halt its progression. Sirtuin 6 (SIRT6) has recently emerged as a promising therapeutic target for vascular calcification. Our prior work demonstrated that SIRT6 activation inhibits vascular calcification by attenuating the osteogenic trans differentiation of vascular smooth muscle cells (VSMCs). While the natural compound cyanidin can activate SIRT6, its clinical translation is hampered by poor bioavailability and the absence of targeted delivery systems. To address this, we developed a dual targeting nanoplatform (TROC) based on Ti₃C₂ nanosheets co-assembled with osteocalcin (OCN) and RANKL antibodies for the targeted delivery of cyanidin. Leveraging data from the Framingham Heart Study offspring cohort and in vitro VSMC models, we first established dietary anthocyanins as an independent protective factor against aortic calcification. We then demonstrated that TROC exhibits excellent stability and dose-dependently reduces calcium deposition in VSMCs. Furthermore, in vivo fluorescence and computed tomography (CT) multimodal imaging confirmed the selective accumulation of TROC at calcification sites and its efficacy in alleviating vascular calcification. This novel drug delivery system represents a promising strategy for advancing the clinical treatment of Vascular calcification.
Hydrogels, as three-dimensional hydrophilic polymer networks, have been widely utilized in biomedical applications due to their excellent biocompatibility, high water content, and tunable physicochemical properties. However, traditional bulk hydrogels often suffer from limitations such as inadequate mechanical strength, slow response to external stimuli, and restricted diffusion efficiency, which hinder their performance in dynamic biological environments. To overcome these challenges, hydrogel microspheres (HMs) have emerged as a promising alternative, which offers advantages such as injectability, high surface-area-to-volume ratio, and tunable functionality. By integrating natural and synthetic materials with advanced fabrication techniques, including microfluidics and emulsification, researchers have achieved precise control over the morphology, size, and bioactivity of HMs. In recent years, stimuli-responsive HMs have attracted significant attention for their ability to respond intelligently to environmental cues such as pH, reactive oxygen species (ROS), enzymes, and temperature. This enables controlled drug release, enhanced therapeutic precision, and spatiotemporal regulation in biomedical applications. This review systematically summarizes the materials, fabrication strategies, and functional mechanisms of stimuli-responsive HMs, highlighting their applications in drug delivery, disease treatment, and tissue engineering. Furthermore, key challenges and future perspectives are discussed, which provides insights into how these intelligent HMs can advance personalized medicine and clinical translation.
Precision oncology urgently requires multifunctional nanoplatforms capable of integrating therapy, diagnosis, and immune modulation to overcome tumor heterogeneity and therapeutic resistance. Vitamin-derived nanomaterials, the intrinsic biocompatibility, metabolic activity, and receptor-targeting properties of vitamins, have emerged as versatile tools to address these challenges, particularly within the immunosuppressive tumor microenvironment (TME). This review critically examines recent advances in vitamin-based nanoplatforms, categorizing them by solubility: fat-soluble vitamins (A, D, E, and K) and water-soluble vitamins (B complex, and C). We explore their roles across three critical domains: (i) immunomodulation, including enhancing cancer immunotherapy by activating dendritic cells, reprogramming T-cells, enhancing checkpoint blockade, inhibiting M2 macrophage polarization, regulating T-cells, upregulating anticancer immunity, and remodeling the TME; (ii) stimuli-responsive drug delivery, exploiting vitamin-derived carriers for tumor-specific payload release and spatiotemporal delivery of antigens/adjuvants; and (iii) diagnostic integration, utilizing vitamin-conjugated imaging probes and theranostic hybrids. In addition, we highlight key preclinical breakthroughs demonstrating that these platforms enhance immunotherapeutic efficacy while minimizing toxicity. However, emerging challenges such as scalability, reproducibility, stability, long-term biodistribution, and clinical translatability are systematically analyzed. By synthesizing mechanistic insights, translational progress, and future directions, this review provides a roadmap for leveraging vitamin biology to engineer next-generation nanomedicines for precision cancer management.
This study explores the development and characterization of iron oxide nanoclusters (NCs) functionalized with vascular cell adhesion molecule 1 (VCAM-1) for targeted magnetic resonance imaging (MRI) of early atherosclerotic lesions. The NCs were synthesized via a high-temperature polyol method and functionalized using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) chemistry to enable conjugation with VCAM-1 antibodies. Dynamic light scattering and transmission electron microscopy TEM confirmed controlled growth of NCs with a size ranging from 40 nm, in the parent to 110 nm post-functionalization, maintaining though colloidal stability in aqueous media. Cytotoxicity assays using mesenchymal stem cells (MSCs) demonstrated high biocompatibility. Confocal and electron microscopy confirmed specific binding of VCAM-1-NCs to VCAM-1-overexpressing MSCs under inflammatory conditions, with internalization through the endolysosomal pathway. The functionalized NCs remained bound under shear stress in an orbital flow model, mimicking early atherosclerotic conditions. MRI phantom analysis demonstrated preserved contrast capability despite increased T 2 * relaxation times following antibody conjugation. These findings highlight the potential of VCAM-1-NCs as noninvasive imaging agents for early-stage atherosclerosis and vascular inflammation. Although this study is limited by the lack of in vivo validation and therapeutic evaluation, it provides a strong foundation for future translational research.
