Acta biomaterialia最新文献

{"title":"A metal-organic framework-based trilayer biomimetic coating on lacrimal stents for dual-drug therapy to prevent restenosis.","authors":"Guanghong Zhang, Luying Liu, Binjian Wang, Hongyi Luo, Wanting Lu, Ruijue Peng, Cheng Zhang, Xiaoqi Pan, Yanni Luo, Zhanfeng Wang, Rui Feng, Chao Qu","doi":"10.1016/j.actbio.2026.05.004","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.05.004","url":null,"abstract":"<p><p>Postoperative reocclusion remains a major challenge in lacrimal duct stent implantation, primarily driven by persistent inflammation and fibrosis. To address this issue, we developed a coating system that integrates drug release with interfacial bioactivity regulation. A polydopamine-hybridized zeolitic imidazolate framework (pZIF-8) was synthesized via a one-pot method and co-loaded with mometasone furoate (anti-inflammatory) and verteporfin (anti-fibrotic) to construct a reactive oxygen species (ROS)/pH responsive nanocarrier. A trilayered coating consisting of a polydopamine (PDA) adhesive layer, a drug-loaded pZIF-8 middle layer, and an outermost hyaluronic acid (HA) antifouling layer was assembled on a silicone stent using a layer-by-layer approach. In vitro, the coating exhibited significantly reduced protein adsorption and bacterial adhesion compared to Control, supported >75% viability of epithelial cells (RPMI 2650) while reducing macrophage (RAW 264.7) viability to approximately 2% and fibroblast (L929) viability to below 50% of Control, and achieved sustained drug release under inflammatory conditions (pH 6.0 + 0.1 mM H₂O₂). In a rabbit lacrimal duct model, the coated stent attenuated acute inflammation, reduced collagen deposition, and downregulated YAP1 expression compared to bare stents. Immunofluorescence analysis showed that bare stents promoted M2a macrophage polarization, whereas the coated stent promoted M2b polarization, as indicated by negative CD68/CD206 colocalization. These findings demonstrate a coating system that combines a ROS/pH-responsive nanocarrier with an antifouling surface to target inflammation and fibrosis. This approach may offer a strategy for preventing stent restenosis and could be adapted for other implantable luminal devices. STATEMENT OF SIGNIFICANCE: Lacrimal stent implantation is frequently complicated by restenosis due to postoperative inflammation and fibrosis. Current stents serve as passive mechanical supports and do not actively intervene in this pathological process. Here we report a metal-organic framework (MOF)-based trilayer coating designed to address both inflammation and fibrosis. The coating consists of a polydopamine adhesive layer, a pZIF-8 MOF layer co-loaded with mometasone furoate (anti-inflammatory) and verteporfin (anti-fibrotic), and an outermost hyaluronic acid antifouling layer. The pZIF-8 nanocarrier exhibits ROS/pH-responsive degradation, while the HA outer layer provides sustained release and antifouling properties. This design may offer a strategy to prevent restenosis and could inform the design of other implantable luminal devices.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A microenvironment-responsive, injectable, and conductive hydrogel integrated with a catalytic nanozyme with ROS scavenging, anti-inflammation, and pro-angiogenic capabilities for synergistic myocardial infarction therapy.","authors":"Huiyuan Zheng, Luxin Feng, Huan Xin, Futai Du, Yangqing Wang, Weijiang Wang, Qingming Ma, Junjie Guo, Wentao Sun","doi":"10.1016/j.actbio.2026.05.005","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.05.005","url":null,"abstract":"<p><p>Myocardial infarction (MI) often leads to adverse ventricular remodeling, a major precursor to heart failure, while current clinical approaches remain limited in effectively promoting myocardial regeneration and suppressing fibrosis. To address these challenges, we developed an injectable, smart-responsive hydrogel integrated with catalytic nanozyme and conductive components for synergistic MI repair. The hydrogel is constructed using phenylboronic acid-modified oxidized hyaluronic acid (OHA-PBA) and dopamine-grafted gelatin (GelDA) as the backbone, cross-linked via dynamic Schiff base and boronate ester bonds, conferring rapid self-healing and specific MI microenvironment-responsive properties. This biomimetic network not only replicates the structure and function of the native extracellular matrix but also responds specifically to the acidic and highly reactive oxygen species (ROS) microenvironment within the infarcted zone, enabling on-demand drug release. Incorporated into the hydrogel are black phosphorus nanosheets (BP Ns) to restore electrical conductivity, and puerarin-loaded honeycomb-like manganese dioxide nanozymes (PHMP NPs) that act as both ROS scavengers and in situ oxygen generators. Together, these components work synergistically to promote angiogenesis, alleviate local hypoxia, and reestablish blood and oxygen supply to the ischemic tissue. This integrated platform thus concurrently delivers mechanical support, restores electrical signaling, alleviates hypoxia, and combines antioxidant, anti-inflammatory, pro-angiogenic, and anti-fibrotic capabilities, offering a comprehensive multi-target therapeutic strategy for MI. Both in vitro and in vivo evaluations demonstrate that the developed hydrogel can effectively inhibit pathological ventricular remodeling, enhance vascularization, and modulate inflammatory responses, with histopathological and transcriptomic analyses further confirming these therapeutic effects, thereby significantly promoting the recovery of cardiac functions and offering a promising and advanced therapeutic strategy for MI treatment. STATEMENT OF SIGNIFICANCE: This work presents an injectable hydrogel platform that uniquely integrates electrical conductivity, catalytic oxygen generation, and smart microenvironment responsiveness for myocardial infarction (MI) therapy. Its significance lies in overcoming the limitation of current single-target approaches by enabling a synergistic multi-functional therapy. The system simultaneously restores electrical conduction, scavenges reactive oxygen species, alleviates hypoxia, and inhibits fibrosis within the infarcted heart. This integrated biomaterial strategy establishes a new paradigm for addressing the complex pathophysiology of MI, offering broad interest to researchers in biomaterials science, cardiac tissue engineering, and regenerative medicine.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microenvironment-adaptive mechano-chemical nanoagent powered by ultrasound for on-demand antibacterial therapy.","authors":"Guopeng Xu, Danfeng Xiong, Yunshan Fan, Lili Niu, Tingting Zhang, Rui Ma, Wenyan Zhang, Yiheng Tang, Dongqing Lin, Xusheng Yang, Jinfeng Yan, Qianyu Wu, Qun Wang, Baozhu Jia, Paul K Chu, Guomin Wang","doi":"10.1016/j.actbio.2026.05.003","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.05.003","url":null,"abstract":"<p><p>Developing a mode-switchable, non-antibiotic platform targeting specific bacterial infection stages is essential for precise antibacterial therapy while minimizing drug resistance. Herein, we present an ultrasound-responsive nanoagent based on BiOCl nanosheets doped with Fe (UBF), capable of adapting to different infection states via switching from mechanical antibacterial mode to mechano-chemical mode. In the early infection, UBF exhibits a mechanical mode to eliminate dominant planktonic bacteria through ultrasound-induced propulsion, causing extracellular membrane disruption and intracellular oxidative stress. Additionally, it physically inhibits biofilm formation by preventing bacterial aggregation and reducing their secretion of critical components (eDNA and polysaccharides) for extracellular polymeric substances (EPS), thus preventing the infection from worsening. Once biofilms mature, endogenous hydrogen peroxide (H₂O₂) triggers the transition to mechano-chemical mode, where UBF catalyzes H₂O₂ into reactive oxygen species (ROS), the yield of which can be further enhanced by ultrasound. Concurrently, ultrasound disrupts the EPS matrix, allowing for deeper ROS penetration, killing bacteria within biofilms. This antibacterial strategy demonstrates self-adaption in vivo, preventing acute lung infections based on mechanical mode and achieving 97.1% healing efficiency for wound with chronic biofilm infections based on mechano-chemical mode. These findings highlight the potential of precision medicine, allowing treatment customization based on infection stages for improved healthcare outcomes. STATEMENT OF SIGNIFICANCE: This study develops an ultrasound-responsive nanoagent (UBF) that autonomously switches bactericidal modes to adapt to different infection stages. For planktonic bacteria, UBF is powered by controllable ultrasound to initiate a potent mechanical mode, achieving bacterial eradication through extracellular physical shearing and intracellular oxidative stress, while physically inhibiting biofilm formation by disrupting bacterial aggregation and EPS secretion. When encountering mature biofilms, UBF automatically transitions into a mechano-chemical mode activated by the overexpressed H₂O₂ in the infection microenvironment. Ultrasound further amplifies this synergistic mode, enabling UBF to mechanically perforate the dense EPS matrix and chemically eradicate deep-seated bacteria. This adaptive, antibiotic-free strategy demonstrates superior efficacy in both acute and chronic infection models, providing an advanced paradigm for combating multidrug-resistant infections.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rocket propulsion-inspired two-stage nitric oxide-releasing hydrogel for phase-matched therapy of diabetic wounds.","authors":"Tuo Chen, Dongna Xie, Yue Wang, Yujia Xu, Pingping Jiao, Jiapan Yan, Rongqian Chen, Meng Wang, Jingjie Shang, Bingyu Ran, Zijing Feng, Dong Ma, Guowei Li, Genlong Jiao","doi":"10.1016/j.actbio.2026.05.002","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.05.002","url":null,"abstract":"<p><p>The healing of diabetic foot ulcers (DFUs) is critically impaired by a self-perpetuating cycle of bacterial infection and chronic inflammation, rendering single-phase therapeutic strategies ineffective. To dynamically address these distinct pathological challenges, we designed a sequentially acting nitric oxide (NO)-releasing hydrogel inspired by the stage-separation principle of rocket propulsion. The hydrogel, formed by crosslinking NO-loaded polyethyleneimine (PEI-NO) with oxidized hyaluronic acid, provides a sharp initial NO release (Stage I). A subsequent sustained release phase (Stage II) is achieved through the combined contribution of residual PEI-NO and encapsulated S-nitrosated cholesterol liposomes (Lip-SNO), with the kinetics tunable via the PEI-NO/Lip-SNO ratio. In vivo experiments demonstrated that this sequential release profile drove a biphasic healing response: the initial NO burst eradicated bacteria and quelled early inflammation, while the sustained NO release during the later stage continuously improved the wound immune microenvironment, promoted macrophage polarization toward the M2 phenotype, increased vascular endothelial growth factor expression, enhanced angiogenesis, and facilitated collagen deposition and tissue remodeling. Consequently, this two-stage sequential release strategy significantly accelerated wound closure in a DFU model, indicating that precise temporal control of NO dosage and release profiles according to disease stage represents an effective strategy for precision therapy of DFU wounds. STATEMENT OF SIGNIFICANCE: Infected diabetic foot wounds are complex chronic conditions for which current treatments mainly rely on antibiotics and local wound management; however, their therapeutic efficacy is often limited by insufficient drug penetration, infections caused by drug-resistant bacteria, and the difficulty of resolving persistent inflammation. Nitric oxide (NO), owing to its broad-spectrum antibacterial activity, immunomodulatory effects, and ability to promote angiogenesis and tissue regeneration, has shown considerable potential in the treatment of diabetic wounds. Nevertheless, diabetic wound healing is highly stage dependent, and material systems capable of delivering NO in a manner matched to disease progression remain insufficiently explored. To address this challenge, this study proposes a rocket-inspired, stage-matched NO delivery strategy and develops a lipid hydrogel system with sequential NO release to achieve precise regulation and synergistic therapy across different healing stages of infected diabetic foot wounds.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virtual fluorescent labeling of engineered vascular networks with embedded tracer particles.","authors":"Sarah Eldeen, Michelle Lanterman, Andres Felipe Guerrero Ramirez, Peter D Chang, Elliot L Botvinick","doi":"10.1016/j.actbio.2026.04.059","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.04.059","url":null,"abstract":"<p><p>Functional microvascular networks in engineered tissues depend on coordinated endothelial-stromal interactions and evolving extracellular matrix (ECM) mechanics, yet fluorescent staining precludes longitudinal studies and is incompatible with repeated particle-based microrheology and traction force measurements. We develop a deep-learning virtual labeling approach that recovers nuclear, cytoskeletal, and endothelial fluorescence from label-free images acquired in fibrin scaffolds. Human umbilical vein endothelial cells and lung fibroblasts were co-cultured in three-dimensional (3D) fibrin hydrogels containing 2μm silica microbeads that can be used to probe local matrix mechanics. Paired transmission and confocal fluorescence z-stacks (DAPI, phalloidin, UEA I) were used to train a 3D U-Net to generate virtual nuclei, actin, and vascular channels directly from bead-containing label-free volumes. To match channel-specific morphology, edge- and structure-preserving losses were assigned to phalloidin and UEA I, while a sparsity-aware loss was applied to DAPI, improving reconstruction quality across mean squared error, structural similarity, peak signal-to-noise ratio, and correlation. Virtual phalloidin preserved fibrillar density and orientation, virtual UEA I reproduced vessel continuity and density without false matrix labeling, and virtual DAPI enabled nuclei segmentation with Dice scores and total cell counts indistinguishable from ground truth (GT). Microbeads did not generate spurious signal in any channel, demonstrating robustness to scattering particles. Together, these results show that virtual fluorescent labeling can replace destructive staining for quantifying fibrillar architecture, vessel density, and cell number in bead-laden fibrin constructs, and establish a practical route toward longitudinal studies of coupled microvascular morphogenesis and ECM mechanics. Statement of Significance Fluorescent staining is widely used to study vascular growth dynamics in biomaterials but requires destructive fixation, preventing repeated measurements in the same sample. We introduce a label-free deep learning approach that predicts multiple fluorescence markers in fully three-dimensional fibrin hydrogels undergoing capillary morphogenesis. Unlike prior virtual staining methods focused on 2D samples, our model operates in thick, optically complex 3D co-cultures and is robust to highly scattering micron-scale tracer beads used for particle-based micromechanical measurements. A channel-specific loss design preserves sharp boundaries and filament continuity, enabling accurate vascular morphometrics and cell-type identifications that are directly interchangeable with measurements from destructive staining. This approach supports non-destructive, quantitative analysis in tissue-engineering experiments and is extensible to other 3D extracellular matrices.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Postoperative Administration of Mesenchymal Stem Cells Enhances Peri-Implant Tissue Healing in a Medication-Related Osteonecrosis of the Jaw Model.","authors":"JiBin, Ikiru Atsuta, Ikue Narimatsu, Tingyu Xie, Yohei Jinno, Akira Takahashi, Yasunori Ayukawa","doi":"10.1016/j.actbio.2026.04.063","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.04.063","url":null,"abstract":"<p><p>Patients undergoing antiresorptive therapy are generally advised against dental surgical procedures, particularly implant placement, due to the high risk of medication-related osteonecrosis of the jaw (MRONJ). Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into multiple lineages; they also regulate immune responses and tissue repair. Previous studies have demonstrated that MSCs alleviate MRONJ symptoms and promote peri-implant tissue healing, although their activation depends on specific in vivo conditions. In this study, we compared the effects of MSC administration before and after implantation on peri-implant hard and soft tissue healing in a rat MRONJ model. In vivo, preoperative MSC treatment did not result in significant differences in peri-implant bone or soft tissue healing compared with the drug-only group, whereas postoperative MSC treatment significantly improved multiple parameters; some reached levels comparable to those of controls. In vitro, postoperative MSC treatment modified the biological characteristics of primary oral epithelial cells and influenced the secretion of key reparative proteins. These findings suggest that postoperative MSC administration enhances peri-implant tissue healing and modulates epithelial cell function, providing new experimental evidence for preventing and treating implant-associated MRONJ. STATEMENT OF SIGNIFICANCE: Medication-related osteonecrosis of the jaw (MRONJ) limits safe implant therapy in patients taking antiresorptive drugs. Using a reproducible MRONJ-like rat model, we show that postoperative, but not preoperative, mesenchymal stem cell (MSC) administration improves peri-implant healing. Postoperative MSCs strengthen epithelial sealing, enhance angiogenesis, reduce neutrophil infiltration, and lessen necrotic bone, with congruent micro-CT and histology. We also report the first isolation and analysis of primary oral epithelial cells from MRONJ peri-implant tissue, revealing MSC-driven gains in proliferation, survival, and barrier proteins. These findings identify therapeutic timing as a key design parameter for MSC-based interventions and provide translational guidance for mitigating implant-associated MRONJ risk, while informing broader biomaterials strategies that couple immunomodulation with repair of the epithelial-implant interface.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrasound-responsive bacteria-nanocomplex reverses tumor resistance to sensitize chemotherapy/chemodynamic therapy in triple-negative breast cancer.","authors":"Renjie Feng, Meng Du, Mingjie Li, Xinlu Zhang, Binrui Shi, Sheng Wang, Zhiyi Chen","doi":"10.1016/j.actbio.2026.04.061","DOIUrl":"10.1016/j.actbio.2026.04.061","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer is in urgent need of precise and effective therapeutic regimens due to drug resistance, which was mainly caused by increased drug efflux based on P-glycoprotein. Therefore, there is an urgent need for precisely regulated therapeutic strategies to reverse tumor drug resistance.</p><p><strong>Results: </strong>This study developed an ultrasound-responsive bacterial-nanocomplex △E@PtkDOX-Fe NMs which was able to achieve ideal chemotherapy/chemodynamic therapeutic effect. The experiments showed that △E@PtkDOX-Fe NMs could be ultrasonically modulated to promote reactive oxygen species production, which in turn inhibited the expression of P-glycoprotein in 4T1/ADR cells (P < 0.05) and increased the intracellular accumulation of DOX (P < 0.05), thereby reducing the activity of drug-resistant tumor cells by 63.19% (P < 0.001) and inhibiting the growth of drug-resistant tumors in vivo (P < 0.01).</p><p><strong>Conclusion: </strong>In this study, we successfully constructed an ultrasound-responsive bacterial-nanocomplex that can increase the local reactive oxygen species level in tumors and thus reverse tumor drug resistance, which provides a method for accurate and controllable reversal of tumor drug resistance, and establishes a mode of accurate and efficient reversal of tumor drug-resistant sensitizing chemotherapy/chemodynamic therapy.</p><p><strong>Statement of significance: </strong>This study developed an ultrasound-responsive bacterial-nanocomplex (△E@PtkDOX-Fe NMs) to overcome P-gp-mediated drug resistance in tumor cells. The complex actively targets tumors via engineered bacterial properties, increasing Fe²⁺ levels in the tumor microenvironment. Meanwhile, △E can upregulates NDH-II levels under ultrasound to elevate H₂O₂ levels, which enhances the Fenton reaction between Fe²⁺ and H₂O₂ to boost ROS generation. These effects trigger DOX release and suppress P-gp expression, sensitizing tumor cells to chemotherapy and improving chemodynamic therapy (CDT) outcomes. This work establishes a spatiotemporally controllable, cascade-amplified combined treatment modality for drug-resistant tumors.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stiffness-engineered hydrogels drive neural regeneration via the Man2b1- lysosomal mechanotransduction axis.","authors":"Fang Liu, Mengjie Xu, Yingxin Wei, Yi Cao, Jiawen Xin, Chunzhen Jiang, Yumeng Ren, Xiuyu Wen, Yixuan Zhao, Feng Li, Li Li, Yifan Li, Yumin Yang, Jianghong He","doi":"10.1016/j.actbio.2026.04.057","DOIUrl":"10.1016/j.actbio.2026.04.057","url":null,"abstract":"<p><p>Peripheral nerve repair requires biomaterials capable of dynamically guiding neural cells. While stiffness-tunable hydrogels hold promise, how their mechanical properties translated into pro-regenerative intracellular signals remains poorly understood. To address gap, we developed a library of polyacrylamide/chitosan hydrogels with tunable stiffness (1.5∼39 kPa) to mimic the native neural microenvironment. Using this platform, we identified an optimal stiffness (∼13.75 kPa) that maximizes PC12 cell adhesion, spreading, neurite outgrowth, and migration. When fabricated into nerve guidance conduits and implanted in rat sciatic nerve defects, hydrogels with this optimal stiffness promoted axonal regeneration and functional recovery to a significantly greater extent than their softer or stiffer counterparts. Transcriptomic analysis further revealed coordinated upregulation of lysosomal and focal adhesion-related genes, with the lysosomal α-mannosidase Man2b1 identified as a core mechanosensitive regulator. We demonstrated that Man2b1 converts optimal matrix stiffness into enhanced lysosomal activity and stable nanoscale adhesion complexes (e.g., FAK, Vinculin). Importantly, genetic ablation of Man2b1 disrupted this mechano-transduction cascade and abolished the pro-regenerative effects of the optimized hydrogel both in vitro and in vivo. Collectively, this study establishes stiffness-engineered hydrogels as a robust platform for peripheral nerve repair and uncovers a fundamental mechano-transduction axis-the Man2b1-lysosome-adhesion signaling cascade-that governs neural regeneration. Our findings highlight how rational biomaterial design can precisely modulate cellular machinery to advance functional tissue engineering. STATEMENT OF SIGNIFICANCE: Peripheral nerve injuries often lead to permanent disability due to the limited regenerative capacity of adult neurons and the lack of biomaterials that can effectively guide repair. While substrate stiffness is known to influence cell behavior, translating this knowledge into effective nerve guides requires both identifying an optimal mechanical range and understanding the underlying cellular mechanisms. This study addresses this dual challenge by first engineering a tunable chitosan-based hydrogel platform to discover a pro-regenerative stiffness. More importantly, we leverage this material system to uncover a previously unknown mechano-transduction pathway-the Man2b1-lysosome-adhesion axis-that is essential for translating optimal mechanical cues into neuronal growth and regeneration. This work therefore provides not only a promising material strategy for advanced nerve guides but also a fundamental mechanobiological principle that could inform the design of biomaterials for a wide range of regenerative applications.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lightweight, elastic and bioactive scaffolds with enhanced vascularization and anti-inflammation for post-enucleation orbital reconstruction.","authors":"Tong Lin, Yiwei Shen, Yue Tan, Xuetian Wen, Wushuang Wang, Yujia Liu, Dong Lei, Hongya Zeng, Lan Gong","doi":"10.1016/j.actbio.2026.04.044","DOIUrl":"10.1016/j.actbio.2026.04.044","url":null,"abstract":"<p><p>Ocular destructive surgery serves as the definitive treatment for irreversible severe damage to intraorbital structures. However, complications such as chronic inflammation, tissue compression, and displacement caused by traditional orbital implant materials significantly impair the life quality of patients in the long term. In this study, we developed a silk fibroin super-elastic sponge (SF-SEA) orbital implant featuring a microporous spherical structure, designed to provide intraorbital structural support and promote tissue regeneration. The orbital implant incorporates a double- crosslinking silk fibroin network and ice-templating micropores, thereby forming a biocompatible, hydrophilic, and lightweight scaffold with tissue ingrowth capability. Exosomes isolated from human urine-derived stem cells (hUSCs) could be conveniently loaded into the scaffold to form bioactive SF-SEA@exo orbital implant, which exhibits sustained exosome release and significantly promotes the proliferation, migration, and angiogenic capacity of human umbilical vein endothelial cells (HUVECs). In the rabbit enucleation and reconstruction model, SF-SEA@exo promoted effective vascular infiltration and displayed anti-inflammatory effects when compared with clinically used traditional hydroxyapatite prostheses. Consequently, the proposed SF-SEA@exo shows promise as an orbital implant for eyeball removal therapy, with substantial transformative potential for clinical translation. STATEMENT OF SIGNIFICANCE: This research has developed a bioactive orbital implant based on silk fibroin super-elastic sponge loaded with exosomes from human urine-derived stem cells (SF-SEA@exo). With porous structure, natural eyeball-like density and sustained exosome release, the prosthesis promoted angiogenesis and tissue regeneration after enucleation more effectively than the traditional hydroxyapatite implants, and controlled the inflammation of the surrounding tissue.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoplasmic Reticulum-Targeted Photodynamic Therapy Synergizes with Rapamycin to Induce Autophagic Cancer Cell Death.","authors":"Yaxin Zheng, Min Su, Shuyao Zhou, Tingting Zhang, Yanqun Wu, Keming Xu, Wenying Zhong","doi":"10.1016/j.actbio.2026.04.062","DOIUrl":"https://doi.org/10.1016/j.actbio.2026.04.062","url":null,"abstract":"<p><p>Autophagy plays a dual role in cancer progression, and strategies to drive excessive autophagic flux remain a promising yet challenging therapeutic avenue. Herein, we develop an endoplasmic reticulum (ER)-targeted self-assembling peptide system (P-1-ERT@Rap) that enables localized photodynamic damage and robust ER stress, which synergizes with rapamycin (Rap) for inducing dual autophagy activation in cancer cells. The peptide P-1-ERT co-assembles with Rap into well-dispersed micelles, which exhibit pH-responsive morphological transformation from nanoparticles to nanofibers under acidic conditions, thereby facilitating lysosomal escape and cellular release of therapeutics. Importantly, P-1-ERT selectively accumulates in the ER and generates reactive oxygen species under laser exposure, triggering significant ER stress with upregulation of CHOP proteins. Concurrently, cellular delivery of Rap, an autophagy inducer, further amplifies autophagic flux with increasing LC3B-II/I ratios, ultimately promoting programmed cell death in A375 cells. Notably, the P-1-ERT@Rap system achieves higher tumor accumulation compared to free photosensitizer in vivo. Moreover, intravenous administration of P-1-ERT@Rap alongside laser irradiation significantly inhibits tumor growth in an A375-xenografted mouse model, with minimal systemic toxicity observed. This dual modulation strategy for autophagy regulation effectively enhances photodynamic therapy efficacy, and it offers a promising approach for exploiting organelle specific stress pathways in cancer treatment. STATEMENT OF SIGNIFICANCE: This study presents a endoplasmic reticulum (ER)-targeted self-assembling peptide nanoplatform (P‑1‑ERT@Rap) that integrates organelle-specific photodynamic therapy (PDT) with autophagy modulation for synergistic cancer treatment. The system uniquely exploits pH-responsive morphological transformation from micelles to nanofibers in acidic tumor environments, facilitating lysosomal escape and efficient intracellular delivery. By selectively accumulating in the ER and generating localized reactive oxygen species upon irradiation, it induces severe ER stress and upregulates CHOP, while co-delivered rapamycin further amplifies autophagic flux. This dual activation of autophagy leads to enhanced programmed cell death in melanoma cells, as demonstrated both in vitro and in vivo. Our work provides a pioneering strategy for organelle-precise therapy that leverages dual stress pathways to overcome the limitations of conventional monotherapies. We believe that this new approach has the potential to revolutionize the field of precision oncology, setting a new paradigm for significantly enhancing treatment outcomes across a broad spectrum of tumor types.</p>","PeriodicalId":93848,"journal":{"name":"Acta biomaterialia","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}