With the growth of the older adult population and the increasing incidence of traumatic injuries, the use of orthopedic devices has risen significantly. However, in addition to material-related limitations, one of the most serious challenges associated with these devices is the risk of infection. To address this issue, an innovative hydrogel is presented to prevent infection at the source during orthopedic surgery. This hydrogel combines polyhexamethylene biguanide (PHMB), a positively charged agent with proven broad-spectrum antimicrobial activity, with a thermosensitive polymer. The resulting formulation provides suitable viscosity for application or dip-coating onto orthopedic devices, thereby forming a stable physical and chemical barrier. The new hydrogel exhibits temperature-responsive viscosity, which enhances both adherence and controlled release at body temperature. Additionally, the hydrogel demonstrates antibacterial effectiveness against both Gram-positive and Gram-negative bacteria, along with low cytotoxicity, minimal immune response, and excellent anti-biofouling properties. These features make the developed hydrogel well suited for orthopedic surgical procedures and support its potential as a complementary approach to reducing the risk of postoperative infections.
Impaired blood-testis barrier (BTB) integrity, induced by oxidative stress, is one of the primary factors leading to spermatogenic disorders in cryptorchidism. Therefore, the targeted elimination of testicular oxidative stress and repair of the BTB are promising strategies for promoting spermatogenesis in patients with cryptorchidism. This study aimed to demonstrate the potential of Sertoli cell membrane-camouflaged biomimetic vesicles loaded with resveratrol carbon dots (RCD@PCy@EVs) as a therapeutic nanoagent for cryptorchidism treatment in vivo. The prepared RCD@PCy@EVs are actively targeted to the seminiferous tubules by leveraging the homing tendency of the Sertoli cell membrane, guided by fluorescence imaging. The RCD@PCy@EVs not only reshape the redox microenvironment of the seminiferous tubules and alleviate inflammatory responses by scavenging reactive oxygen species, but they also increase the expression of the tight junction protein β-catenin and restore BTB integrity, which is associated with the activation of the SIRT1/AMPKα/FOXO1 signaling pathway. More importantly, functional spermatogenesis is markedly improved by RCD@PCy@EVs, effectively restoring reproductive function in cryptorchid mice. The RCD@PCy@EVs-mediated therapy for cryptorchidism offers a novel strategy for treating male infertility.
Hydrogels have emerged as promising candidates for next-generation implantable biomedical stents. However, the scalable fabrication of hydrogel three-dimensional (3D) stents with sufficient mechanical support remains a major challenge, owing to the intrinsic flexibility of hydrogel materials. Here, inspired by the water-welding mechanism of the butterfly proboscis, we report a facile water-mediated welding strategy for sodium alginate (SA) films, which enables the assembly of fully integrated 3D stents using only water as the processing medium. The as-prepared solid-walled 3D stents can be seamlessly converted into hollow-walled architectures via a metal ion-induced asymmetric crosslinking followed by solvent exchange. Notably, the hollow-walled structure enables the mechanical support force five times that of solid-walled ones, rendering these hydrogel 3D stents highly attractive for biodegradable medical stents. This work provides a versatile and environmentally benign route to engineer 3D hydrogel stents, thereby advancing the development of advanced implantable biomedical devices.
The blood-brain barrier (BBB), while indispensable for maintaining central nervous system (CNS) homeostasis, constitutes the principal impediment to effective therapeutic delivery for neurodegenerative disorders, particularly hindering spatially resolved modulation of extracellular ions and reactive oxygen species (ROS) within the neural microenvironment. Contemporary electrochemical methodologies have emerged as a paradigm shift for dynamically reconciling these dual parameters, thereby enabling targeted neuroregulation. Critical review of this field reveals a distinct evolution from passive physiological interventions to active electrochemical engineering approaches. Current research, however, encounters persistent translational barriers including insufficient spatiotemporal resolution in neural interfaces, incomplete mechanistic understanding of ROS-ionic crosstalk, and scalability limitations of nanoscale delivery systems. To transcend these limitations, the synergistic convergence of electrochemical platforms with machine learning (ML)-guided predictive analytics, near-infrared (NIR) phototherapy, and biocompatible nanocarrier-mediated delivery systems constitutes a strategic imperative in next-generation neurotherapeutic development. Such interdisciplinary convergence is not merely incremental but rather a fundamental prerequisite for realizing clinically translatable neural microenvironment modulation.
Magnetically driven biofabrication is emerging as a materials-enabled extension of tissue engineering, integrating advances in magnetic nanoparticle (MNP) design with cells, spheroids, and biomaterial scaffolds to engineer responsive and remotely controllable living systems. Progress in nanoparticle engineering has yielded biocompatible and tunable MNP formulations that can be incorporated into hydrogels, spheroids, organoids, and scaffolds, where they influence cellular behavior, extracellular matrix organization, and mechanotransduction. Externally applied magnetic fields further enable non-contact control over cell positioning, microtissue assembly, matrix alignment, and dynamic mechanical stimulation, expanding the design space of 3D and 4D biofabrication. This Review critically maps and unifies the multiscale design principles underlying magnetically driven biofabrication, spanning nanoparticle design, magnetic actuation strategies, and biological responses. We compare approaches ranging from single-cell manipulation and magnetoactive bioinks to spheroid fusion and microfluidic systems with embedded magnetic actuation. We further discuss how physics-based modeling, data-informed optimization, and emerging digital twin concepts may help connect material properties, magnetic field design, and biological response. Finally, we examine translational considerations, including Good Manufacturing Practice (GMP)-compatible nanoparticle formulations, mechanistic clarity, long-term safety evaluation, and regulatory alignment, converging toward magnetically enabled tissue-engineered advanced therapy medicinal products (Mag-TE ATMPs).
Traditional hydrogel dressings face challenges like poor adhesion and limited antibacterial effects. We developed a biocompatible polyacrylamide-DNA double-network hydrogel (AuPt/PEDOT-DNA gel), cross-linked by bis-acrylamide and DNA duplexes, offering softness, stretchability, and self-adhesiveness for direct skin application. Incorporating AuPt/PEDOT, a cascade nanozyme with peroxidase/oxidase-mimicking activities and high photothermal efficiency, enables dual antibacterial action via ROS generation and photothermal therapy. Under near-infrared irradiation, it achieves > 95% bacterial killing at safe concentrations and inhibits biofilm formation. Moreover, the intrinsic conductivity of the AuPt/PEDOT-DNA gel enables its operation as a flexible strain sensor that transduces skin deformation into motion signals, which can be harnessed to monitor periwound mechanical strain and provide active feedback to prevent excessive tissue tension, thereby complementing the antimicrobial and drug-delivery functions with biomechanical protection during rehabilitation. It conforms to wounds, prevents drug leakage, and eradicates bacteria, enhancing prospects for advanced hydrogel dressings.
Secondary injury after traumatic brain injury (TBI) is characterized by excessive reactive oxygen species (ROS) production and persistent neuroinflammation, which remain difficult to control using a single therapeutic agent. Herein, a dissolvable microneedle platform based on Prussian blue (PB) nanoparticles was developed to locally deliver curcumin (Cur) or edaravone (EDA) into injured brain tissue through a transiently disrupted blood-brain barrier. The microneedles were fabricated from hyaluronic acid/carboxymethyl chitosan (HCMN) using a low-temperature multilayer drying process while maintaining the structural integrity of PB nanoparticles. Acting as both ROS-scavenging nanozymes and drug carriers, PB nanoparticles enabled flexible incorporation of different therapeutic agents within the same delivery platform. In vitro and in vivo studies showed that HCMN/PB/Cur exhibited greater anti-inflammatory activity under relatively mild pathological conditions, whereas HCMN/PB/EDA displayed stronger antioxidant capacity under higher oxidative stress. These results suggest that different therapeutic formulations may be preferable under distinct pathological conditions while preserving the same delivery platform. This microneedle system provides a localized delivery approach and offers greater flexibility for formulation selection in the treatment of acute TBI.
Osteoporotic fractures pose a significant clinical challenge in aging societies due to the limited efficacy and high re-fracture risk associated with conventional treatments. To address this, we developed EXOs@ECM-SCS, a multifunctional bioactive hydrogel that encapsulates exosomes derived from induced pluripotent stem cell-induced mesenchymal stem cells within a hybrid matrix of decellularized extracellular matrix and methacrylated sulfated chitosan. This composite system promotes bone regeneration through a synergistic strategy that concurrently targets angiogenesis, immunomodulation, neurogenesis, and osteogenesis (AINO). Experimental results demonstrated that EXOs@ECM-SCS significantly enhanced osteogenic differentiation, angiogenic activity, and neural regeneration, while also driving macrophage polarization toward the M2 phenotype. These multifaceted effects collectively improved bone mass accumulation, mineralization, and fracture healing in an osteoporotic mouse model. Mechanistic insights from exosomal sequencing highlighted the involvement of key miRNAs such as miR-100-5p and miR-320a-3p, along with PI3K-Akt and MAPK signaling pathways. These findings underscore EXOs@ECM-SCS as an innovative therapeutic platform that leverages coordinated multimodal regulation to accelerate osteoporotic fracture repair.
Prostate cancer (PCa) is the most prevalent malignancy in men, often progressing to a more refractory form castration-resistant prostate cancer (CRPC) after primary androgen deprivation therapy. Immunotherapy has brought new hope to PCa patients, but the immunosuppressive characteristics of PCa cells limit its efficacy. Cuproptosis, which can affect tumorigenesis, therapeutic resistance, and immune modulation has received significant attention recently. However, it is limited by insufficient copper ion (Cu2+) concentration, hypoxia, and overexpression of glutathione (GSH) in tumors. To overcome these limitations, a targeted nanoplatform (CuS@MYC-PEG-FA) is fabricated to achieve a synergistic cuproptosis and immunotherapy. CuS@MYC-PEG-FA can not only promote reactive oxygen species (ROS) generation and Cu2+ release, but also elicit a powerful antitumor immunity response. Meanwhile, the loaded c-MYC inhibitor (MYCMI-6) can reduce the expression of glutaminase and subsequently inhibit the generation of GSH, further sensitizing cells to cuproptosis effectively. Notably, cuproptosis combined with photothermal therapy (PTT) can turn the "cold" tumor properties of PCa into "hot" ones, leading to its sensitivity to anti-programmed death ligand 1 (anti-PD-L1) immunotherapy. The results show that the combination of CuS@MYC-PEG-FA and PD-L1 inhibitor treatment can significantly inhibit the development of PCa, providing a new strategy for the treatment of PCa.
The integration of vascular and peripheral nerve components into bioengineered human skin equivalents (HSEs) represents a major advancement in regenerative medicine and biomedical research. While research has established vascularized HSE models, the role of neurovascular interactions in skin physiology and pathophysiology remains underexplored, particularly in translational or clinical contexts. These interactions are crucial for sensory perception, nutrient transport, thermoregulation, and immune modulation, making the development of vascularized and innervated HSE an important goal. Here, we first describe the anatomical and physiological roles of the vascular and peripheral nerve systems in the skin, focusing on their intricate relationships and significance to illnesses. This review then highlights recent advancements in engineering vascular and nerve structures in HSE, including strategies such as transwell-based systems, 3D bioprinting, and organ-on-chip models. Despite significant progress, challenges remain in establishing functional neurovascular networks, achieving long-term stability, and ensuring reproducibility. By addressing these challenges, neurovascularized HSE can enhance our understanding of skin physiology and pathology while advancing applications in disease modeling, drug testing, wound healing, and personalized medicine.
This study aims to develop pH-sensitive GelAgar-GA hydrogels composed of Gum Arabic (GA)-incorporated gelatin and agarose for wound healing applications. Our results reveal that the agarose content modulates the structural, chemical, physical, and biological properties of hydrogels. Noticeably, the hydrogel containing 3 wt% agarose (GelAgar-GA-3) shows optimized characteristics, including superior elastic modulus (186 ± 12 kPa) and tensile strength (173 ± 12 kPa), mimicking the mechanical properties of native skin. The swelling ability of this hydrogel is modulated via pH changes. Noticeably, the water absorption capacity of GelAgar-GA-3 at pH = 5 is 247 ± 47%, which increases to 327±45% at pH = 9. GelAgar-GA hydrogels also indicate significant coagulation ability, low hemolysis (<5%), and decreased bleeding compared to the control. In vitro studies reveal that GelAgar-GA hydrogel could accelerate the proliferation and migration of fibroblasts and shows significant antibacterial activity, following doxycycline encapsulation (GelAgar-GA-3(Dox)). In vivo studies on a rat model also show 99% wound closure in full-thickness wounds treated with GelAgar-GA-3(Dox), attributed to the reduced inflammatory response and promoted vascular remodeling, maturation, and collagen deposition, thereby resulting in accelerated wound repair. In summary, these results demonstrate that the GelAgar-GA-3(Dox) is a favorable system for wound healing applications.
Extracellular vesicles (EVs) have gained recognition as crucial mediators of cell-to-cell communication, holding immense potential in diverse biomedical applications. Nanoarchitectonics, a multidisciplinary approach encompassing nanotechnology and biomedicine, offers novel strategies for manipulating EVs at the nanoscale. This review explores the transformative influence of nanoarchitectonics on EVs research, focusing on the current progress in integrating various nanostructures to engineer EVs for enhanced therapeutic and diagnostic capabilities. The application of nanoarchitectonics has led to the fabrication of specialized nanostructures, such as plasmonic, fluorescent, magnetic, carbon-based, and organic-framework-based nanostructures designed explicitly for EVs research. This approach enables the engineering of EVs with improved targeting specificity, cargo loading efficiency, and therapeutic efficacy, thus advancing their potential in precision medicine. The review addresses the opportunities and challenges associated with the convergence of nanoarchitectonics and EVs research, underscoring the necessity for further optimization, rigorous safety assessments, and interdisciplinary collaboration. Finally, the review concludes by discussing the strengths and limitations of the nanoarchitectonics-EVs interface in nanomedicine and therapeutics, providing a strategic roadmap for future advancements in this rapidly evolving field.
Combining efficient photocatalytic activity with precise targeting is crucial for covalent organic framework (COF)-based nanomedicines to remodel the immunosuppressive microenvironment and sensitize "cold" tumors to immunotherapy. Herein, we constructed two isomorphic frameworks featuring distinct electronic topologies: a zwitterionic squaric acid (SA) COF with inherent electrostatic asymmetry, and a charge-neutral terephthaldehyde (TA) COF. The spatial divergence of ion centers in SA COF triggers intense molecular-level ionic displacement polarization, creating a robust internal electric field. Such unique field-effect regulation accelerates photogenerated charge separation for efficient superoxide anion production, enhances intersystem crossing for singlet oxygen generation, and promotes nonradiative energy relaxation for high-performance photothermal conversion under dual-wavelength irradiation. After PEGylation and iRGD modification, the formulated SA@PEG-iRGD exhibits excellent physiological stability and active deep tumor penetration. With near-infrared absorption, it enables high-contrast photoacoustic imaging for guided dual-wavelength (660/808 nm) phototherapy. This spatiotemporally controlled therapeutic cascade triggers lethal ferroptosis and precise photothermal ablation, potently activating immunogenic cell death. Combined with aPD-L1 therapy, it eliminates primary tumors, produces abscopal effects, and establishes immune memory against recurrence and metastasis. This study highlights the value of electronic structure engineering in COF-based precision nanomedicine.
Inflammatory bowel disease (IBD) and its frequent hepatic complication, metabolic-associated steatohepatitis (MASH), are intrinsically linked through the dysregulated gut-liver axis, with intestinal barrier dysfunction serving as a central pathological driver. Coordinated therapy that restores barrier integrity and interrupts pathogenic gut-liver crosstalk remains a significant challenge. To address this, a colon-targeted delivery system based on sodium alginate microspheres is developed for loading copper-kaempferol nanocomplexes (CuK@SA). Upon oral administration, this system prolongs the retention and release of CuK NCs in the colon. Through scavenging reactive oxygen and nitrogen species (ROS/RNS), regulating macrophage polarization, improving microbial homeostasis, and enhancing tight junction protein expression, it multi-dimensionally restores intestinal barrier integrity and effectively blocks the translocation of endotoxins to the liver via the gut-liver axis. In mouse models of dextran sulfate sodium (DSS)-induced colitis and high-fat-diet-induced MASH, CuK@SA significantly alleviates intestinal inflammation, repairs barrier structure, and simultaneously improves hepatic steatosis and inflammatory responses. This work provides a novel strategy for synchronously targeting IBD and its systemic complications through modulation of the gut-liver axis.
Injectable hydrogels used in tissue engineering and minimally invasive therapies are limited by insufficient biocompatibility, poor scalability, high costs, and inconsistent performance. Here, we introduce gelatinized starch, a common polysaccharide, as a versatile and economical building block to expand the existing repertoire of injectable hydrogel materials. Derived from native corn starch via heating and gelatinization, this biopolymer exhibits shear-thinning, thixotropic, and thermoreversible sol-gel transition properties, key rheological characteristics essential for syringeability and in situ structural recovery. It readily integrates with photo-crosslinkable (e.g., GelMA, HAMA, AlgMA) and ionically crosslinkable (e.g., alginate, chitosan) hydrogels. Rheological tests confirm that starch incorporation imparts excellent injectability, rapid gelation, and robust structural recovery. Bone marrow mesenchymal stem cells (BMSCs) encapsulated in starch-based composite hydrogels maintained high viability, showed enhanced protein expression, and exhibited strong proliferation, which were modulated by starch concentration and cell seeding density. Notably, injection depth influenced post-delivery cell viability within the hydrogel, whereas injection width had no significant effect. In a rat femoral condyle defect model, injection of a BMSC-laden gelatinized starch hydrogel markedly promoted bone regeneration. Collectively, gelatinized starch overcomes key limitations of conventional injectable hydrogels, providing a cost-effective, biocompatible, and functionally adaptable platform for cell delivery and tissue regeneration.
Photothermal therapy (PTT) as a localized cancer treatment modality has gained considerable momentum recently. While conventional PTT relies on photothermal agents (PTAs) to produce abundant heat (above 50°C) via near-infrared (NIR) laser irradiation for tumor ablation, this high-temperature approach often inflicts collateral thermal injury on surrounding healthy tissues, which severely constrains the therapeutic feasibility of PTT near vital organs. Therefore, mild-temperature PTT (below 45°C) is of clinical interest. Herein, we construct an injectable hydrogel (IVH@gel) via the coordination between calcium ions (Ca2 +) and sodium alginate to encapsulate the PTA Hu Kaiwen Ink, the free radical initiator 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (VA-044), and the autophagy inhibitor hydroxychloroquine (HCQ) for realizing synergistic PTT and immunotherapy. Specifically, when irradiated under an NIR laser, the ink in the hydrogel generates heat, which leads to the degradation of VA-044 to produce free radicals for killing cancer cells; meanwhile, HCQ is released for realizing autophagy-inhibited mild-temperature PTT of tumor. More importantly, the IVH@gel-mediated PTT elicits strong immunogenic cell death (ICD), which activates a potent antitumor immune response, leading to significant tumor inhibition. This work provides a promising method for the development of multifunctional mild-temperature PTT drugs.
Metabolic-associated steatohepatitis (MASH) remains difficult to treat due to the lack of interventions capable of targeting upstream disease drivers and achieving durable disease modification. The epigenetic regulator Mrg15 has been implicated in mitochondrial dysfunction and metabolic stress in the liver, suggesting its potential relevance to MASH pathogenesis. Here, we develop a liver-targeted lipopolymer nanoparticle (LPNP)-mediated gene editing platform to enable in vivo disruption of Mrg15 by co-delivery of Cas9 mRNA and Mrg15 sgRNA. The screened P64H/Mrg15 system achieved efficient hepatic delivery and genome editing, resulting in reduced Mrg15 expression in hepatocytes. In the MASH mouse model, P64H/Mrg15 treatment was associated with decreased hepatic lipid accumulation, improved liver injury markers, and attenuation of inflammation and fibrosis. Sequence-level analyses confirmed on-target editing in liver tissue, and systemic histopathological evaluation revealed no overt toxicity in major organs under the tested dosing regimen. Transcriptomic profiling revealed coordinated pathway-level associations involving metabolic, inflammatory, and autophagy-related regulation, while protein-level analyses demonstrated alterations in selected autophagy- and mitophagy-related regulators, including TUFM and LC3B-II. Together, these findings identify Mrg15 as a disease-relevant epigenetic regulator in MASH and highlight liver-directed P64H LPNP/CRISPR delivery as a promising non-viral strategy for modulating upstream regulatory pathways in metabolic liver disease.
The delayed healing of diabetic wounds involves both impaired efferocytosis and dysfunctional phosphatidylserine (PS) receptor signaling, leading to macrophage defects in migration, persistent M1 polarization, and diminished cellular resilience. To address this multifaceted pathology, a bioactive wound dressing was developed by incorporating PEGylated RGD-grafted phosphatidylserine liposomes (PEG/RGD-PSLs) into a photocrosslinkable hyaluronic acid methacryloyl (HAMA) hydrogel matrix. This platform provides sustained, delivery of a biomimetic "eat-me" signal while actively reprogramming macrophage behavior. Under diabetic-mimicking stress conditions, PEG/RGD-PSLs significantly enhanced macrophage migration, promoted M1-to-M2 phenotypic transition, and conferred robust cytoprotection by preserving mitochondrial integrity, attenuating oxidative stress, and suppressing pathological extracellular vesicle release. Mechanistically, PS binding upregulated the inhibitory receptor CD300a, which suppressed the MyD88/NF-κB pathway and downregulated pro-inflammatory genes. Critically, siRNA-mediated CD300a knockdown abolished these anti-inflammatory and NF-κB-suppressive effects, establishing CD300a as necessary for therapeutic action. In a diabetic rat model, a single application of the bioactive hydrogel significantly accelerated wound closure, stimulated angiogenesis, improved organized collagen deposition, and actively shifted the wound immune microenvironment toward a pro-reparative M2-dominant state. Collectively, this study identifies the PS/CD300a/NF-κB axis as a key regulatory node for rescuing macrophage dysfunction and establishes a functionally active hydrogel-based therapy for chronic diabetic wounds.
A biodegradable biomimetic nanoplatform (HMCDL@TK-M) was constructed by combining hydrogen-doped HxMoO3 nanoparticles, dual-drug loading, and a hybrid spinach-cancer cell membrane coating. The system features pH-responsive biodegradability, tumor-homing capability, and high NIR-II photothermal conversion. An oxygen-lactate cascade, formed via thylakoid membrane-mediated H2O2 decomposition and lactate oxidase-driven lactate oxidation, alleviates hypoxia and depletes lactate in the tumor microenvironment. This dual metabolic modulation reprograms M2 macrophages to M1, promotes dendritic cell maturation, and reduces Treg infiltration. In 4T1 tumor-bearing mice, HMCDL@TK-M achieves strong tumor accumulation, effective photothermal ablation, and combined with lactate depletion, complete tumor eradication without systemic toxicity. The treatment also induces robust CD4+/CD8+ effector memory T-cell responses, providing durable antitumor immunity. This work demonstrates a synergistic metabolic-photothermal immunotherapy strategy for efficient and long-lasting cancer treatment.
