ACS Biomaterials Science & Engineering最新文献

{"title":"Structure-Guided CDR3 Insertion Enables Affinity Maturation of Naive Single-Domain Antibodies against Small-Molecule Haptens","authors":"Zenglin Yang,&nbsp;Guoqiang Li,&nbsp;Yuanyuan Ge,&nbsp;Xin Liu,&nbsp;Limin Cao,&nbsp;Kaiqiang Wang,&nbsp;Xiudan Wang,&nbsp;Hong Lin,&nbsp;Shaoen Zhang,&nbsp;Qingzhou Chen,&nbsp;Jianxin Sui","doi":"10.1021/acsbiomaterials.6c00666","DOIUrl":"10.1021/acsbiomaterials.6c00666","url":null,"abstract":"<p>Single-domain antibodies (sdAbs) derived from naive phage display libraries offer a time-efficient alternative to animal immunization but often exhibit suboptimal affinity, particularly for small-molecule haptens, where restricted binding interfaces limit the efficacy of traditional saturation mutagenesis. For instance, the wild-type sdAb (B1)-targeting ethoxyquin (EQ) exhibits a moderate equilibrium dissociation constant (<em>K</em>_D) at the submicromolar level (within the 10⁻⁷ M range), restricting its practical sensitivity. To overcome the structural and energetic barriers inherent in hapten recognition, a “structure-guided directed modification” strategy was developed that focuses on conformational tuning rather than simple side-chain replacement. Integrating AlphaFold2 modeling and AutoDock mechanistic analysis identified key interactions (e.g., the ASP19-EQ-N8 hydrogen bond). Subsequently, a random single-amino acid insertion strategy was implemented within the CDR3 loop (residues 77−90) to fine-tune local loop geometry. Top candidates were screened via MM/GBSA binding free energy calculations and experimentally validated using biolayer interferometry. This approach yielded three high-affinity mutants—77A, 79C, and 85H—with calculated ΔΔ<em>G</em> values of −10.56, −4.35, and −6.69 kcal/mol, respectively. The mutants achieved enhanced affinities in the tens-of-nanomolar range (down to 35.1 nM), representing up to approximately 3 times overall improvement. Importantly, orthogonal surface plasmon resonance analysis using nonconjugated, free EQ successfully verified this affinity maturation trend, showing that mutant 79C bound free EQ with a <em>K</em>_D of 1.30 × 10⁻⁵ M (a 2.3 times improvement over wild-type) through simultaneously accelerated association and slowed dissociation. Mechanistically, this substantial increase in affinity is attributed not only to reinforced noncovalent networks that significantly stabilize the complex but also to favorable CDR3 geometric outward flips that alleviate steric hindrance, leading to an approximate 3.8 times acceleration in the <em>k</em>_on. Crucially, these mutants demonstrated notable anti-interference tolerance in complex aquatic food matrices (e.g., sea bass extracts). Ultimately, this work provides a practical and efficient computational framework for assisting the rapid evolution of low-affinity hapten sdAbs into high-performing biorecognition elements with potential for next-generation biosensing architectures.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 9","pages":"4720–4733"},"PeriodicalIF":6.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Folic-Acid-Modified Fe-TCPP Metal-Organic Frameworks as Sonosensitive Agents and siATAD3A Carriers for Sonodynamic Co-Gene-Ferroptosis Therapy in Triple-Negative Breast Cancer","authors":"Yang Du,&nbsp;Jiangnan Yang,&nbsp;Shuai Chen,&nbsp;Xiaoxin Yang,&nbsp;Yian Wang,&nbsp;Yiyuan Yang,&nbsp;Deyuan Fu","doi":"10.1021/acsbiomaterials.6c01047","DOIUrl":"10.1021/acsbiomaterials.6c01047","url":null,"abstract":"<p>Triple-negative breast cancer (TNBC) represents the most aggressive form of breast cancer and is associated with the worst prognosis. Ferroptosis holds great promise as an emerging therapeutic strategy; however, TNBC cells demonstrate reduced sensitivity to ferroptosis as a result of elevated mitochondrial membrane potential (MMP), inadequate production of reactive oxygen species (ROS), and the presence of activated antioxidant defencses, making it difficult for lipid peroxidation to accumulate to a lethal threshold. As an emerging therapeutic strategy, sonodynamic therapy (SDT) is particularly suitable for deep-seated tumors due to the excellent tissue penetration capabilities of ultrasound (US). Nevertheless, current sonosensitizer typically experience limited sonodynamic efficacy and inadequate targeting of tumors, whereas small interfering RNA (siRNA) presents a highly promising option for gene therapy, its efficacy is heavily dependent on efficient and safe cellular delivery vectors. Therefore, we designed and synthesized a folate-modified Fe-TCPP metal-organic framework (FTFA) nanoplatform that serves both as a siATAD3A gene therapy carrier and as a sonosensitizer to generate ROS upon ultrasound (US) irradiation. ATAD3A displays high expression levels in TNBC and is linked to a negative prognosis; it's silencing reduces MMPs and increases ROS-induced apoptosis. siATAD3A was loaded onto FTFA to prepare FTFA@siATAD3A, which was delivered to TNBC cells via folate receptor-mediated targeting. Under US irradiation, the Fe³⁺ loaded within this platform synergistically triggers a ferroptosis cascade involving the Fenton reaction, lipid peroxidation, and GPX4 downregulation, effectively inducing ferroptosis. This method greatly reduces the proliferation of cells, as well as their migration and tumor growth when tested in living organisms, and it also shows excellent compatibility with biological tissues. In summary, FTFA@siATAD3A provides a novel strategy for the synergistic gene-ferroptosis therapy of TNBC using sonodynamic effects.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 9","pages":"4848–4865"},"PeriodicalIF":6.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Steady Cone-Jet Mode of Electrospray for Single-Cell Deposition","authors":"Daniel Fernández-Martínez,&nbsp;Conrado Ferrera Llera,&nbsp;Jose Maria Montanero,&nbsp;Laura Mendoza-Cerezo,&nbsp;Jesús Manuel Rodríguez-Rego","doi":"10.1021/acsbiomaterials.6c00717","DOIUrl":"10.1021/acsbiomaterials.6c00717","url":null,"abstract":"<p>We propose using the electrospray cone-jet mode operated near its minimum-flow-rate stability limit for single-cell deposition. Because the jet is much thinner than the cells themselves, individual cells can be clearly visualized or detected during deposition. At such low flow rates, individual cells could potentially be placed at distinct, user-defined locations, even at relatively high cell concentrations. In this sense, our approach provides a spatial resolution at the scale of a single cell. We demonstrate the method’s capabilities by depositing cells onto a millimeter-scale droplet of a standard cell-culture medium. Cell viability assays indicate that many cells maintain membrane integrity after exposure to the electrosprayed liquid, suggesting that the process can preserve cell integrity in a substantial fraction of cells under the tested conditions.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 9","pages":"5097–5105"},"PeriodicalIF":6.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148682662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Antitumor Photodynamic Therapy Based on Dipeptide Fibrous Hydrogels with Incorporation of Photosensitive Drugs”","authors":"Manzar Abbas,&nbsp;Ruirui Xing,&nbsp;Ning Zhang,&nbsp;Qianli Zou,&nbsp;Xuehai Yan","doi":"10.1021/acsbiomaterials.6c01286","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.6c01286","url":null,"abstract":"","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 9","pages":"5106–5106"},"PeriodicalIF":6.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered Titanium Surfaces with Electrophoretically Deposited Graphene Oxide-Mesoporous Bioglass Nanocoatings for Enhanced Bone Regeneration and Antibacterial Activity","authors":"Kapil D. Patel,&nbsp;Adam W. Perriman,&nbsp;Rajendra K. Singh,&nbsp;Hae-Won Kim","doi":"10.1021/acsbiomaterials.6c00769","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.6c00769","url":null,"abstract":"<p>Multifunctional surface engineering of titanium implants that integrates osteogenic activity with localized antibacterial function is highly desirable yet remains challenging. Here, we report a nanostructured graphene oxide/mesoporous bioactive glass nanoparticle (GO/MBGN) nanocoating fabricated via electrophoretic deposition (EDP) using a chitosan-assisted strategy. An amine-functionalized mesoporous bioactive glass nanoparticle (MBGN-NH₂) enables co-deposition with negatively charged GO, resulting in uniform and stable coatings with tunable nanotopography and composition. Structural and microscopic analyses confirm homogeneous incorporation of MBGN within the GO matrix while preserving the amorphous mesoporous structure, essential for ion release and drug loading. The GO/MBGN nanocoatings significantly enhance cellular responses in a composition-dependent manner. Notably, GO-10MBGN promotes improved cell spreading, focal adhesion, and proliferation of rat bone marrow-derived mesenchymal stem cells. Osteogenic differentiation is markedly upregulated, as evidenced by increased expression of alkaline phosphatase (ALP), collagen type I (COL I), and osteocalcin (OCN), attributed to combined effects of nanoscale surface features and sustained release of Ca²⁺ and SiO₄^4– ions. Furthermore, gentamicin sulfate (GENT)-loaded MBGN endow controlled drug release, exhibiting an initial burst followed by sustained delivery over 6 weeks. This results in effective antibacterial activity against <em>Staphylococcus aureus</em>, with enhanced inhibition observed for higher MBGN content. Collectively, this work establishes that GO/MBGN nanocoatings possess both osteoinductive and antibacterial functionalities, offering a promising strategy for advanced titanium implants.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 9","pages":"4980–4992"},"PeriodicalIF":6.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comparative In Vivo Study of Small-Diameter Vascular Grafts Fabricated from Electrospun Tecothane and Tecoflex Polyurethanes","authors":"Olesia S. Osipova,&nbsp;Ivan S. Murashov,&nbsp;Alena O. Stepanova,&nbsp;Vera S. Chernonosova,&nbsp;Andrey A. Karpenko,&nbsp;Pavel P. Laktionov","doi":"10.1021/acsbiomaterials.6c00724","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.6c00724","url":null,"abstract":"<section><div></div><p>This study aimed to compare the <em>in vivo</em> performance of small-diameter vascular prostheses (VPs) electrospun from protein-enriched aromatic (Tecothane) and aliphatic (Tecoflex) polyurethanes versus standard expanded polytetrafluoroethylene (ePTFE) grafts in a rat aortic model. The unsatisfying long-term patency and excessive neointimal hyperplasia of clinically used ePTFE small-diameter grafts motivate the search for alternative materials with improved biocompatibility and mechanical compliance. SDVGs were implanted into the infrarenal aorta of Wistar rats for up to 6 months. Evaluations included graft patency (Doppler ultrasound), mechanical properties (tensile testing), histology (H&amp;E staining), immunohistochemistry (CD31, α-SMA, and collagen IV), and analysis of neointimal formation as well as peri-graft tissue response. Polyurethane (PU) grafts demonstrated superior surgical handling, with shorter anastomosis times and better needle-puncture sealing than ePTFE. Tecothane grafts exhibited higher tensile strength but lower elasticity than Tecoflex. Both PU grafts maintained stable mechanical properties post-implantation and showed better patency than ePTFE. Notably, neointimal hyperplasia was markedly reduced in PU grafts (2–3-fold increase in thickness vs. 6-fold for ePTFE). Tecothane grafts developed a denser, more organized thinner neointima with a well-defined CD31⁺ endothelial layer and elicited less peri-graft tissue encapsulation than Tecoflex. Critically, no calcification was observed in any PU grafts, unlike ePTFE controls. The electrospun Tecothane graft demonstrated an optimal balance of mechanical properties, biocompatibility, and hemodynamic performance, favoring rapid endothelialization and suppressing pathological remodeling (excessive neointimal hyperplasia and calcification). These results support Tecothane SDVG as a promising alternative to ePTFE for small-diameter vascular replacement.</p></section>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 9","pages":"4967–4979"},"PeriodicalIF":6.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered Deoxyribonucleic Acid-Tunable Spheroid Platform for Analysis of Tumor-Macrophage Interactions","authors":"Sven A. Saemundsson,&nbsp;Taylor R. Ausec,&nbsp;Bryce M. Bower,&nbsp;Shane D. Curry,&nbsp;C. Wyatt Shields IV,&nbsp;Andrew P. Goodwin,&nbsp;Jennifer N. Cha","doi":"10.1021/acsbiomaterials.6c00195","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.6c00195","url":null,"abstract":"<p>Tumor architecture strongly influences immune cell behavior, yet the individual contributions of cell-cell spacing and hypoxia remain difficult to isolate <em>in vivo</em>. Here, we use a DNA-programmable 3D tumor spheroid platform to generate 4T1 spheroids with tunable intercellular spacing and predictable hypoxia gradients, enabling structural and biochemical cues to be decoupled. Using this system, we compared infiltration and polarization dynamics of immortalized RAW 264.7 macrophages and primary BMDMs. Macrophages readily infiltrated preformed spheroids across all DNA lengths, indicating that the packing differences achievable here do not impose a major physical barrier. Instead, infiltration kinetics were cell-specific, where BMDMs penetrated more rapidly and reached maximal infiltration by 24 h, while RAW macrophages infiltrated more slowly. Soluble factors released by spheroids induced a modest pro-inflammatory shift in 2D controls, confirming contact-independent activation. Within spheroids, RAW macrophages exhibited hypoxia-dependent polarization at 24 h, with lower hypoxia promoting higher CD80/CD206 ratios. This effect equalized by 48 h. BMDMs showed more muted and hypoxia-insensitive responses, with inflammation peaking around 24 h and gradually resolving. These results establish DNA-engineered spheroids as a powerful system for dissecting how cell spacing and hypoxia regulate macrophage behavior.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 9","pages":"4734–4745"},"PeriodicalIF":6.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper-Containing Surface Engineering for Soft-Tissue Biomedical Devices: Structure−Function Relationships and Ion Release-Driven Biological Performance, A Systematic Review","authors":"Agnieszka Słodkowska,&nbsp;Anna Sierosławska,&nbsp;Robert Mroczka","doi":"10.1021/acsbiomaterials.6c00568","DOIUrl":"https://doi.org/10.1021/acsbiomaterials.6c00568","url":null,"abstract":"<p>Copper and copper-based materials have gained increasing attention for the functional modification of implantable medical devices intended for prolonged soft-tissue contact, including vascular stents, catheters, and intrauterine devices. Owing to their broad-spectrum antimicrobial activity, redox reactivity, and involvement in angiogenesis and cellular signaling, copper-based systems offer significant potential for multifunctional surface engineering. However, achieving a balance between antibacterial efficacy, corrosion behavior, controlled ion release, and cytocompatibility remains a critical challenge. This PRISMA-compliant systematic review analyzes copper-containing materials and surface modification strategies for soft-tissue biomedical applications. A structured search of Scopus, Web of Science, and PubMed (2015–2025) identified 65 eligible studies. The review encompasses bulk copper-containing alloys, electrochemical and chemical surface modification techniques, physical vapor deposition approaches, and advanced hybrid systems integrating copper with polymers, hydrogels, or metal−phenolic networks. Across the reviewed literature, antibacterial performance was strongly dependent on copper concentration, microstructural distribution, and spatiotemporal ion release profiles. Moderate, well-controlled copper incorporation frequently improved antibacterial efficacy while maintaining acceptable hemocompatibility and cytocompatibility, particularly in vascular and blood-contacting devices. In contrast, excessive copper loading often accelerated corrosion and induced adverse cellular responses. Emerging multifunctional architectures demonstrated improved regulation of biological interactions, enabling simultaneous antibacterial, antithrombotic, and proendothelial effects. Overall, copper-based surface technologies represent a versatile platform for soft-tissue implant modification. Future translational progress will require precise control of copper release kinetics and comprehensive long-term <em>in vivo</em> validation to ensure safety and sustained therapeutic performance. From the authors’ perspective, the most promising future direction involves multifunctional copper-based hybrid coatings capable of dynamically regulating ion release, host tissue integration, and antibacterial performance simultaneously. Strategies integrating hierarchical architectures, stimulus-responsive release systems, and clinically scalable fabrication methods are expected to play a key role in translating copper-containing surfaces from experimental concepts toward commercially viable soft-tissue biomedical devices.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 9","pages":"4611–4645"},"PeriodicalIF":6.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Domain Coordination Governs Pore Architecture in Transient Double-Network Antibody-Binding Polyprotein Hydrogels","authors":"Sanam Bista,&nbsp;M A Mohaiminul Islam,&nbsp;Ionel Popa","doi":"10.1021/acsbiomaterials.6c00634","DOIUrl":"10.1021/acsbiomaterials.6c00634","url":null,"abstract":"<p>Protein-based hydrogels synthesized from covalently cross- linked globular proteins are an emerging class of biomaterials, yet their dense nanoscale network architecture severely limits permeability to large biomolecules. Here, we report a general strategy to create highly permeable polyprotein hydrogels by photochemically cross-linking engineered octameric repeats of antibody-binding Protein A or Protein L in the presence of a transient alginate network, which can function as high-capacity affinity matrices. We demonstrate that the coordination capacity per domain controls the cross-linked shell that forms around growing pores during competitive gelation, with higher coordination (Protein L) producing a denser shell and more numerous but smaller pores and lower coordination (Protein A) yielding larger pores. The resulting hydrogels enable rapid and deep penetration of antibodies throughout the entire material volume while retaining high functional-domain density. When used as model affinity matrices, these materials display exceptional binding capacity, near-quantitative recovery, and excellent operational and shelf stability. This work establishes a molecular design rule for tuning porosity in folded-protein biomaterials and opens a route to next-generation, fully protein-based scaffolds with programmable permeability and function.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 9","pages":"5087–5096"},"PeriodicalIF":6.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microfluidic Engineered Gelatin Methacryloyl Microsphere Scaffolds Loaded with Extracellular Vesicles Derived from Mesenchymal Stromal Cells Promote Functional Recovery in Rats with Spinal Cord Injury","authors":"Haoyu Sheng,&nbsp;Yihe Wang,&nbsp;Yijing Zhao,&nbsp;Sashuang Liu,&nbsp;Dexiang Liu,&nbsp;Zhen Wang","doi":"10.1021/acsbiomaterials.6c00661","DOIUrl":"10.1021/acsbiomaterials.6c00661","url":null,"abstract":"<p>Spinal cord injury (SCI) leads to significant locomotor, sensory, and autonomic deficits and remains refractory to current therapies. Extracellular vesicles from mesenchymal stromal cells (MSC-EVs) are potential acellular therapeutic strategy for tissue regeneration, but rapid clearance and poor lesion retention limit their efficacy; combining MSC-EVs with biomaterial depots can improve local retention and sustained release. Here, we engineered porous gelatin methacryloyl (GelMA) microspheres using a self-designed simple microfluidic device. MSC-EVs were physically loaded into porous GelMA microspheres, which were subsequently embedded into a GelMA scaffold to form GelMA microsphere-embedded GelMA scaffolds loaded with MSC-EVs (GMS-EVs scaffolds). Based on the satisfactory elastic modulus, suitable porous organized structure, and good biocompatibility, the GMS-EVs scaffolds could achieve local retention and sustained release of MSC-EVs both in vivoand in vitro. Implantation of GMS-EVs scaffolds showed significantly improved motor recovery, reduced glial scar formation, and enhanced neuronal regeneration compared to both SCI and GelMA-only controls in a rat spinal cord hemisection model. Mechanistically, these beneficial effects of GMS-EVs scaffolds were associated with the stimulation of the phosphoinositide 3-kinase/protein kinase B (PI3K-AKT) and extracellular signal-regulated kinase (ERK) signaling pathways in SCI rats. Overall, this study highlights the potential of scaffolds based on porous GelMA microspheres combined with MSC-EVs to enhance tissue repair in the injured spinal cord environment.</p>","PeriodicalId":8,"journal":{"name":"ACS Biomaterials Science & Engineering","volume":"12 9","pages":"4951–4966"},"PeriodicalIF":6.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148756757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}