Pub Date : 2026-01-22DOI: 10.1016/j.biomaterials.2026.124016
Zeguo Chen , Zhongshi Wu , Can Huang , Qiying Wu , Chao Xie , Sicheng Chen , Liang Yi , Haoyong Yuan , Sixi Liu , Abdulraheem Mustapha , Siyao Chen , Wansong Chen , Ting Lu , Zhenjie Tang , Yuhong Liu
Delayed endothelialization and inadequate matrix remodeling remain major obstacles in the development of small-diameter vascular grafts (SDVGs; <6 mm). To address these challenges, we developed an immunomodulatory tissue-engineered vascular graft (iTEVG) by integrating hollow mesoporous silica nanoparticles (HMSNs) with tailored mesopore sizes as delivery carriers for immunoregulatory factors. VEGF was selectively immobilized on the intimal surface, while the adventitia incorporated a sequential release system for VEGF and IL-4. VEGF exhibited rapid release (64.04 ± 4.44 % in 7 days), promoting monocyte recruitment and adventitial neovascularization, while IL-4 showed sustained release (65.94 ± 2.06 % over 28 days), driving long-term M2 macrophage polarization. In rats, iTEVGs achieved 88 % endothelial coverage and smooth muscle cell infiltration within 1 month, full-thickness cellularization with a complete trilaminar structure by 3 months, and maintained mechanical integrity without aneurysm formation up to 6 months. This spatially partitioned platform, built on an acellular vascular scaffold, enables precise spatiotemporal regulation of the immune microenvironment and offers a design paradigm that synergistically promotes endothelialization and vascular matrix remodeling. The “intima-targeted regeneration and adventitia-sequential-release” strategy provides a promising template for SDVG design that may be extended to other complex organ constructs.
{"title":"Spatiotemporally programmed VEGF/IL-4 delivery via HMSNs enhances endothelialization and immune-mediated matrix remodeling in acellular vascular grafts","authors":"Zeguo Chen , Zhongshi Wu , Can Huang , Qiying Wu , Chao Xie , Sicheng Chen , Liang Yi , Haoyong Yuan , Sixi Liu , Abdulraheem Mustapha , Siyao Chen , Wansong Chen , Ting Lu , Zhenjie Tang , Yuhong Liu","doi":"10.1016/j.biomaterials.2026.124016","DOIUrl":"10.1016/j.biomaterials.2026.124016","url":null,"abstract":"<div><div>Delayed endothelialization and inadequate matrix remodeling remain major obstacles in the development of small-diameter vascular grafts (SDVGs; <6 mm). To address these challenges, we developed an immunomodulatory tissue-engineered vascular graft (iTEVG) by integrating hollow mesoporous silica nanoparticles (HMSNs) with tailored mesopore sizes as delivery carriers for immunoregulatory factors. VEGF was selectively immobilized on the intimal surface, while the adventitia incorporated a sequential release system for VEGF and IL-4. VEGF exhibited rapid release (64.04 ± 4.44 % in 7 days), promoting monocyte recruitment and adventitial neovascularization, while IL-4 showed sustained release (65.94 ± 2.06 % over 28 days), driving long-term M2 macrophage polarization. In rats, iTEVGs achieved 88 % endothelial coverage and smooth muscle cell infiltration within 1 month, full-thickness cellularization with a complete trilaminar structure by 3 months, and maintained mechanical integrity without aneurysm formation up to 6 months. This spatially partitioned platform, built on an acellular vascular scaffold, enables precise spatiotemporal regulation of the immune microenvironment and offers a design paradigm that synergistically promotes endothelialization and vascular matrix remodeling. The “intima-targeted regeneration and adventitia-sequential-release” strategy provides a promising template for SDVG design that may be extended to other complex organ constructs.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124016"},"PeriodicalIF":12.9,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.biomaterials.2026.124012
Lingxiao Jin , Liang Chen , Yucheng Xue , Keye Chen , Shixin Chen , Kelei Wang , Fangqian Wang , Guoxin Qu , Zhenxuan Shao , Shenzhi Zhao , Haochen Mou , Hao Zhou , Zengjie Zhang , Xiayu Hu , Jiangchu Lei , Fanglu Chen , JianBin Xu , Peng Zhang , Binghao Li
Neutrophils have emerged as promising candidates for next-generation immunotherapies against solid tumors. However, the physical barrier formed by tumor-induced neutrophil extracellular traps (NETs) significantly restricts the migration and infiltration of circulating immune cells, thereby limiting their anti-tumor efficacy. This study demonstrated tumors driven NET formation.
within recruited neutrophils via the Transforming Growth Factor Beta (TGFβ) signaling pathway. Therefore, a neutrophil-arming nanoplatform (NE@LTT@DNase1) was developed to enable neutrophils to degrade NETs while preserving their innate immune functions. Mechanistically, NE@LTT@DNase1 exerts dual therapeutic effects: (i) enzymatic degradation of pre-existing NETs via neutrophil surface-anchored DNase1 and (ii) spatiotemporal suppression of NETosis via endogenous lysine-trypotophan-threonine peptide (LTT) fragmentation in a reactive oxygen species-dependent manner. Data show that NE@LTT@DNase1 treatment was associated with increased infiltration of NK cells and T cells, as well as a shift of neutrophils and macrophages toward an anti-tumor polarization, collectively contributing to the reversal of the immunosuppressive tumor microenvironment (TME). In combination with anti-Programmed Death-1 (anti-PD-1) therapy, the NE@LTT@DNase1-based immunotherapy strategy resulted in a 74 % reduction in tumor burden and prolonged median survival by 61 % in tumor-bearing mice. Overall, these findings established a next-generation therapeutic paradigm for advanced neutrophil-based immunotherapy (NBI).
{"title":"Spatiotemporal controls of neutrophil extracellular traps boosts neutrophils immunotherapy efficiency against solid tumors","authors":"Lingxiao Jin , Liang Chen , Yucheng Xue , Keye Chen , Shixin Chen , Kelei Wang , Fangqian Wang , Guoxin Qu , Zhenxuan Shao , Shenzhi Zhao , Haochen Mou , Hao Zhou , Zengjie Zhang , Xiayu Hu , Jiangchu Lei , Fanglu Chen , JianBin Xu , Peng Zhang , Binghao Li","doi":"10.1016/j.biomaterials.2026.124012","DOIUrl":"10.1016/j.biomaterials.2026.124012","url":null,"abstract":"<div><div>Neutrophils have emerged as promising candidates for next-generation immunotherapies against solid tumors. However, the physical barrier formed by tumor-induced neutrophil extracellular traps (NETs) significantly restricts the migration and infiltration of circulating immune cells, thereby limiting their anti-tumor efficacy. This study demonstrated tumors driven NET formation.</div><div>within recruited neutrophils via the Transforming Growth Factor Beta (TGFβ) signaling pathway. Therefore, a neutrophil-arming nanoplatform (NE@LTT@DNase1) was developed to enable neutrophils to degrade NETs while preserving their innate immune functions. Mechanistically, NE@LTT@DNase1 exerts dual therapeutic effects: (i) enzymatic degradation of pre-existing NETs via neutrophil surface-anchored DNase1 and (ii) spatiotemporal suppression of NETosis via endogenous lysine-trypotophan-threonine peptide (LTT) fragmentation in a reactive oxygen species-dependent manner. Data show that NE@LTT@DNase1 treatment was associated with increased infiltration of NK cells and T cells, as well as a shift of neutrophils and macrophages toward an anti-tumor polarization, collectively contributing to the reversal of the immunosuppressive tumor microenvironment (TME). In combination with anti-Programmed Death-1 (anti-PD-1) therapy, the NE@LTT@DNase1-based immunotherapy strategy resulted in a 74 % reduction in tumor burden and prolonged median survival by 61 % in tumor-bearing mice. Overall, these findings established a next-generation therapeutic paradigm for advanced neutrophil-based immunotherapy (NBI).</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124012"},"PeriodicalIF":12.9,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.biomaterials.2026.124003
Shuang Wang, Tianwu Chen, Yong Li, Lei Zhang, Jing Wang, Changsheng Liu
The long-term success of anterior cruciate ligament (ACL) reconstruction depends on the stable integration between artificial grafts and host bone. Despite their favorable mechanical strength, polyethylene terephthalate (PET) artificial ligaments often suffer from micromotion-induced fibrosis and persistent foreign body reactions (FBR), which together hinder osteointegration. Here, we develop a dual-network hydrogel coating with time-staged local immunomodulatory capability, enabling functional "mechano-immune" synergy at the graft-bone interface. Catechol-functionalized hyaluronic acid (HAMA-DOP) forms strong adhesive interactions with PET through π-π stacking, hydrogen bonding, and reversible covalent bonds. Subsequent oxidative crosslinking into a dense quinone-based secondary network enhances shear resistance and fatigue durability, while supporting self-healing. Pluronic F127 diacrylate (PF127-DA) introduces a thermoresponsive structure allowing the hydrogel to transition from injectable fluid at 4 °C to a stable gel at 37 °C, enabling localized and phase-specific release of celecoxib (CXB). This facilitates early suppression of inflammation and sustained promotion of regeneration. In vivo studies reveal a dose-dependent regulatory effect of CXB, where low-dose delivery promotes M2 macrophage polarization, H-type vessel formation, and bone bridging, while high doses impair immune homeostasis and osteointegration. This work establishes a robust, biologically responsive interface strategy, advancing the design of innovative coatings for enhanced outcomes in artificial ligament integration.
{"title":"Friction-adaptive hydrogel coating for mechanical-immune synergy in ligament-to-bone integration.","authors":"Shuang Wang, Tianwu Chen, Yong Li, Lei Zhang, Jing Wang, Changsheng Liu","doi":"10.1016/j.biomaterials.2026.124003","DOIUrl":"https://doi.org/10.1016/j.biomaterials.2026.124003","url":null,"abstract":"<p><p>The long-term success of anterior cruciate ligament (ACL) reconstruction depends on the stable integration between artificial grafts and host bone. Despite their favorable mechanical strength, polyethylene terephthalate (PET) artificial ligaments often suffer from micromotion-induced fibrosis and persistent foreign body reactions (FBR), which together hinder osteointegration. Here, we develop a dual-network hydrogel coating with time-staged local immunomodulatory capability, enabling functional \"mechano-immune\" synergy at the graft-bone interface. Catechol-functionalized hyaluronic acid (HAMA-DOP) forms strong adhesive interactions with PET through π-π stacking, hydrogen bonding, and reversible covalent bonds. Subsequent oxidative crosslinking into a dense quinone-based secondary network enhances shear resistance and fatigue durability, while supporting self-healing. Pluronic F127 diacrylate (PF127-DA) introduces a thermoresponsive structure allowing the hydrogel to transition from injectable fluid at 4 °C to a stable gel at 37 °C, enabling localized and phase-specific release of celecoxib (CXB). This facilitates early suppression of inflammation and sustained promotion of regeneration. In vivo studies reveal a dose-dependent regulatory effect of CXB, where low-dose delivery promotes M2 macrophage polarization, H-type vessel formation, and bone bridging, while high doses impair immune homeostasis and osteointegration. This work establishes a robust, biologically responsive interface strategy, advancing the design of innovative coatings for enhanced outcomes in artificial ligament integration.</p>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"124003"},"PeriodicalIF":12.9,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.biomaterials.2026.124011
Wen Li , Li Cao , Jiaqi Zhu , Hui Wang , Yijie Liu , Lingyu Zhang , Chen Guo , Jing Yan , Wenjing Wang , Bo Zhou , Jiangfang Lian , Bo Guo , Chen Huang
Cold atmospheric plasma (CAP) has emerged as a promising non-thermal modality in cancer research due to its ability to induce selective cytotoxicity through reactive oxygen and nitrogen species. However, the limited penetration depth and instability of plasma-derived reactive species in complex biological environments remain major obstacles to its therapeutic application. In this study, we investigated whether exosomes derived from CAP-treated cancer cells (CAP-Exo) could serve as functional mediators to extend and amplify the anti-tumor effects of CAP. Using chronic myeloid leukemia K562 cells as a primary model, we demonstrate that CAP treatment induces pronounced oxidative stress, apoptosis, and sustained proliferative suppression. Importantly, exosomes isolated from CAP-treated cells exhibited enhanced anti-proliferative and pro-apoptotic activity in recipient cells compared to exosomes from untreated controls. To assess the broader applicability of this strategy, we further evaluated the effects of CAP and CAP-Exo in multiple solid tumor models, including breast, renal, and hepatocellular carcinoma cells, both in vitro and in vivo. CAP exposure consistently reduced cell viability across solid tumor cell lines, while CAP-Exo retained potent cytotoxic activity against breast cancer cells and significantly suppressed tumor growth in corresponding xenograft models without inducing systemic toxicity. Mechanistically, CAP-induced stress reprogrammed exosomal cargo, enabling the transfer of death-associated molecular signals to recipient tumor cells and thereby promoting apoptosis. Collectively, our findings indicate that CAP-modified exosomes represent a biologically active, cell-free approach that extends the anti-tumor effects of CAP treatment across both hematological malignancies and solid tumors. Rather than replacing existing therapeutic modalities, CAP-Exo may serve as a complementary strategy to enhance CAP-based cancer interventions and overcome current limitations associated with direct CAP application.
{"title":"Prolonging the anti-tumor effects of cold atmospheric plasma via exosome-mediated signaling","authors":"Wen Li , Li Cao , Jiaqi Zhu , Hui Wang , Yijie Liu , Lingyu Zhang , Chen Guo , Jing Yan , Wenjing Wang , Bo Zhou , Jiangfang Lian , Bo Guo , Chen Huang","doi":"10.1016/j.biomaterials.2026.124011","DOIUrl":"10.1016/j.biomaterials.2026.124011","url":null,"abstract":"<div><div>Cold atmospheric plasma (CAP) has emerged as a promising non-thermal modality in cancer research due to its ability to induce selective cytotoxicity through reactive oxygen and nitrogen species. However, the limited penetration depth and instability of plasma-derived reactive species in complex biological environments remain major obstacles to its therapeutic application. In this study, we investigated whether exosomes derived from CAP-treated cancer cells (CAP-Exo) could serve as functional mediators to extend and amplify the anti-tumor effects of CAP. Using chronic myeloid leukemia K562 cells as a primary model, we demonstrate that CAP treatment induces pronounced oxidative stress, apoptosis, and sustained proliferative suppression. Importantly, exosomes isolated from CAP-treated cells exhibited enhanced anti-proliferative and pro-apoptotic activity in recipient cells compared to exosomes from untreated controls. To assess the broader applicability of this strategy, we further evaluated the effects of CAP and CAP-Exo in multiple solid tumor models, including breast, renal, and hepatocellular carcinoma cells, both <em>in vitro</em> and <em>in vivo</em>. CAP exposure consistently reduced cell viability across solid tumor cell lines, while CAP-Exo retained potent cytotoxic activity against breast cancer cells and significantly suppressed tumor growth in corresponding xenograft models without inducing systemic toxicity. Mechanistically, CAP-induced stress reprogrammed exosomal cargo, enabling the transfer of death-associated molecular signals to recipient tumor cells and thereby promoting apoptosis. Collectively, our findings indicate that CAP-modified exosomes represent a biologically active, cell-free approach that extends the anti-tumor effects of CAP treatment across both hematological malignancies and solid tumors. Rather than replacing existing therapeutic modalities, CAP-Exo may serve as a complementary strategy to enhance CAP-based cancer interventions and overcome current limitations associated with direct CAP application.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124011"},"PeriodicalIF":12.9,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146045957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1016/j.biomaterials.2026.124013
Ning Cong , Lu Guo , Xiaoxuan Wang , Yading Zhao , Ting Zhao , Shuting Huang , Rui Liu , Song Ning , Xiaoying Zhou , Suyun Li , Yuye Fu , Jie Li
Cuproptosis is a novel form of cell death that relies on mitochondrial metabolism and has opened up new avenues for tumor therapy. However, resistance to cuproptosis in tumors can arise from several factors, such as their reliance on aerobic glycolysis, the high-glutathione (GSH) environment, and inefficient copper (Cu) delivery. In this study, we developed shell-core nanodroplets (NDs) approximately 280 nm in diameter, named Cu-EGCG-SHK-NDs. These NDs are composed of a liquid-gas phase-change perfluorohexane core and a carboxymethyl chitosan shell, loaded with the glycolytic inhibitor shikonin (SHK) and coated with Cu-complexed epigallocatechin gallate (Cu-EGCG), enabling targeted delivery through ultrasound (US)-targeted microbubble destruction (UTMD). The dual responsiveness of NDs to both US and pH enables precise drug release and efficient intracellular uptake. In addition, the US response enhances contrast-enhanced US imaging and triggers the generation of reactive oxygen species, subsequently depleting GSH. Both in vitro and in vivo experiments confirm that Cu-EGCG-SHK-NDs possess excellent biocompatibility. Combined with UTMD, they can efficiently co-deliver Cu and SHK into tumour cells, inhibit glycolytic metabolism, and significantly reduce intracellular GSH levels. This synergistic mechanism enhances cuproptosis induction and achieves effective tumour growth inhibition.
{"title":"Ultrasound-activated metal-polyphenol nanodroplets for tumor cuproptosis","authors":"Ning Cong , Lu Guo , Xiaoxuan Wang , Yading Zhao , Ting Zhao , Shuting Huang , Rui Liu , Song Ning , Xiaoying Zhou , Suyun Li , Yuye Fu , Jie Li","doi":"10.1016/j.biomaterials.2026.124013","DOIUrl":"10.1016/j.biomaterials.2026.124013","url":null,"abstract":"<div><div>Cuproptosis is a novel form of cell death that relies on mitochondrial metabolism and has opened up new avenues for tumor therapy. However, resistance to cuproptosis in tumors can arise from several factors, such as their reliance on aerobic glycolysis, the high-glutathione (GSH) environment, and inefficient copper (Cu) delivery. In this study, we developed shell-core nanodroplets (NDs) approximately 280 nm in diameter, named Cu-EGCG-SHK-NDs. These NDs are composed of a liquid-gas phase-change perfluorohexane core and a carboxymethyl chitosan shell, loaded with the glycolytic inhibitor shikonin (SHK) and coated with Cu-complexed epigallocatechin gallate (Cu-EGCG), enabling targeted delivery through ultrasound (US)-targeted microbubble destruction (UTMD). The dual responsiveness of NDs to both US and pH enables precise drug release and efficient intracellular uptake. In addition, the US response enhances contrast-enhanced US imaging and triggers the generation of reactive oxygen species, subsequently depleting GSH. Both <em>in vitr</em><em>o</em> and <em>in vivo</em> experiments confirm that Cu-EGCG-SHK-NDs possess excellent biocompatibility. Combined with UTMD, they can efficiently co-deliver Cu and SHK into tumour cells, inhibit glycolytic metabolism, and significantly reduce intracellular GSH levels. This synergistic mechanism enhances cuproptosis induction and achieves effective tumour growth inhibition.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124013"},"PeriodicalIF":12.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<div><div>Polypropylene mesh (PPM) improves anatomic outcomes in pelvic organ prolapse (POP) repair, yet complications—most commonly pain and mesh exposure—occur in ∼10 % of cases. Clinically, meshes that are implanted flat often demonstrate striking deformation at explanation, including pore collapse and wrinkling. Both computational models and <em>in vivo</em> studies confirm that mesh geometry changes substantially after tensioning during prolapse repair. Although T cells have been implicated in mesh-related complications, the specific impact of mesh deformation on adaptive immunity is not fully understood.</div><div>To address this gap, a lightweight PPM (Restorelle) was implanted in nonhuman primates either in its flat configuration (stable, R0) or engineered into two progressively deformed geometries: R45 (unstable: pore collapsed) and RD (predeformed: pore collapsed + wrinkled). Sham-operated animals served as controls. Twelve weeks post-implantation, mesh–tissue complexes were analyzed to quantify T-cell phenotypes, tissue remodeling, and downstream healing outcomes. Findings were integrated with a comparative proteomic analysis of flat versus deformed human mesh explants.</div><div>Mesh burden increased stepwise with deformation (R0 < R45 < RD). Deformation amplified T-cell infiltration within the vaginal adventitia, with helper T cells dominating and cytotoxic T cells contributing minimally. T<sub>regs</sub> were enriched in the moderately deformed R45 group—consistent with injury resolution—but were markedly reduced in RD, indicating a shift toward chronic, non-resolving inflammation. Whereas flat meshes maintained organized collagen and physiologic fibrotic encapsulation, deformed meshes—particularly RD—exhibited loss of organized ECM, increased fibroblast-driven remodeling, and elevated fibroblast growth factor-2 (FGF-2). Cytokine profiling revealed increased IL-1β and CXCL12 across all mesh groups, but RD uniquely showed suppression of Th2 cytokines (IL-4, IL-5), a signature of impaired immune resolution.</div><div>Human explants mirrored key primate findings: CD99, a marker of T-cell trafficking and persistent activation, was elevated in specimens from patients with complications, while CD84, which mediates T:B-cell interactions and memory formation, was reduced—suggesting repetitive T-cell activation without durable immune regulation.</div><div>Together, these results demonstrate that increasing mesh deformation drives a shift from a Th2/Treg-dominant, pro-resolution immune response toward chronic inflammation characterized by persistent T-cell activation and fibroblast-mediated ECM disruption. This work directly links mesh geometry–induced mechanical stress to adaptive immune dysregulation and disordered collagen remodeling and validates these signatures in human specimens. The findings highlight actionable opportunities for geometry-preserving mesh designs and targeted T-cell–directed immunomodulation to prevent complicati
{"title":"Profiling the T cell response to polypropylene mesh in a non-human primate sacrocolpopexy model","authors":"Srividya Kottapalli , Marrisa Therriault , Rui Liang , Malini Harinath , Gabby King , Pamela A. Moalli , Amanda Artsen","doi":"10.1016/j.biomaterials.2026.124008","DOIUrl":"10.1016/j.biomaterials.2026.124008","url":null,"abstract":"<div><div>Polypropylene mesh (PPM) improves anatomic outcomes in pelvic organ prolapse (POP) repair, yet complications—most commonly pain and mesh exposure—occur in ∼10 % of cases. Clinically, meshes that are implanted flat often demonstrate striking deformation at explanation, including pore collapse and wrinkling. Both computational models and <em>in vivo</em> studies confirm that mesh geometry changes substantially after tensioning during prolapse repair. Although T cells have been implicated in mesh-related complications, the specific impact of mesh deformation on adaptive immunity is not fully understood.</div><div>To address this gap, a lightweight PPM (Restorelle) was implanted in nonhuman primates either in its flat configuration (stable, R0) or engineered into two progressively deformed geometries: R45 (unstable: pore collapsed) and RD (predeformed: pore collapsed + wrinkled). Sham-operated animals served as controls. Twelve weeks post-implantation, mesh–tissue complexes were analyzed to quantify T-cell phenotypes, tissue remodeling, and downstream healing outcomes. Findings were integrated with a comparative proteomic analysis of flat versus deformed human mesh explants.</div><div>Mesh burden increased stepwise with deformation (R0 < R45 < RD). Deformation amplified T-cell infiltration within the vaginal adventitia, with helper T cells dominating and cytotoxic T cells contributing minimally. T<sub>regs</sub> were enriched in the moderately deformed R45 group—consistent with injury resolution—but were markedly reduced in RD, indicating a shift toward chronic, non-resolving inflammation. Whereas flat meshes maintained organized collagen and physiologic fibrotic encapsulation, deformed meshes—particularly RD—exhibited loss of organized ECM, increased fibroblast-driven remodeling, and elevated fibroblast growth factor-2 (FGF-2). Cytokine profiling revealed increased IL-1β and CXCL12 across all mesh groups, but RD uniquely showed suppression of Th2 cytokines (IL-4, IL-5), a signature of impaired immune resolution.</div><div>Human explants mirrored key primate findings: CD99, a marker of T-cell trafficking and persistent activation, was elevated in specimens from patients with complications, while CD84, which mediates T:B-cell interactions and memory formation, was reduced—suggesting repetitive T-cell activation without durable immune regulation.</div><div>Together, these results demonstrate that increasing mesh deformation drives a shift from a Th2/Treg-dominant, pro-resolution immune response toward chronic inflammation characterized by persistent T-cell activation and fibroblast-mediated ECM disruption. This work directly links mesh geometry–induced mechanical stress to adaptive immune dysregulation and disordered collagen remodeling and validates these signatures in human specimens. The findings highlight actionable opportunities for geometry-preserving mesh designs and targeted T-cell–directed immunomodulation to prevent complicati","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124008"},"PeriodicalIF":12.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1016/j.biomaterials.2026.124017
Si-Yong Qin , Wei-Wei Cheng , Meng-Yun Peng , Chuang Cai , Qi Lei , Rong Huang , Yin-Jia Cheng , Wen-Long Liu , Yi-Han Ma , Ai-Qing Zhang , Lei Wang
The aligned microarchitecture of extracellular matrix (ECM) has been recognized as a significant and novel hallmark of certain tumors, which is gradually uncovered to relate to their malignant progression. However, most artificial scaffolds are isotropic and fail to mimic such aligned organization of tumor-associated ECMs. To address this limitation, we developed a self-assembling peptide-based liquid crystal (LC) hydrogel model to recapitulate the aligned topology of tumor ECM, thereby establishing a platform to investigate the relationship between ECM alignment and malignant cell phenotype. The screened peptide self-assembled into aligned nanofibers via a thermal pathway, forming an LC hydrogel with engineered biological properties. When cultured within the peptide LC hydrogel, tumor cells displayed enhanced proliferation, migration, invasion, and drug-resistance, underscoring the critical role of ECM alignment in promoting aggressive phenotypes. Leveraging the LC hydrogel model, we provided initial insights into the mechanisms underlying malignant progression via Western blot, reverse transcription-quantitative PCR and RNA sequencing analyses. Moreover, by implanting LC hydrogel precultured cancer cells into C57BL/6 mice, we established a tumor model exhibiting accelerated growth. Our findings demonstrate that the self-assembled peptide LC hydrogel can recapitulate tumor ECM alignment and enable the development of rapidly progressing tumor models for cancer research and drug screening.
{"title":"Recapitulating tumor extracellular matrix alignment to decipher its role in eliciting malignant cell phenotypes using a peptide liquid crystal hydrogel","authors":"Si-Yong Qin , Wei-Wei Cheng , Meng-Yun Peng , Chuang Cai , Qi Lei , Rong Huang , Yin-Jia Cheng , Wen-Long Liu , Yi-Han Ma , Ai-Qing Zhang , Lei Wang","doi":"10.1016/j.biomaterials.2026.124017","DOIUrl":"10.1016/j.biomaterials.2026.124017","url":null,"abstract":"<div><div>The aligned microarchitecture of extracellular matrix (ECM) has been recognized as a significant and novel hallmark of certain tumors, which is gradually uncovered to relate to their malignant progression. However, most artificial scaffolds are isotropic and fail to mimic such aligned organization of tumor-associated ECMs. To address this limitation, we developed a self-assembling peptide-based liquid crystal (LC) hydrogel model to recapitulate the aligned topology of tumor ECM, thereby establishing a platform to investigate the relationship between ECM alignment and malignant cell phenotype. The screened peptide self-assembled into aligned nanofibers via a thermal pathway, forming an LC hydrogel with engineered biological properties. When cultured within the peptide LC hydrogel, tumor cells displayed enhanced proliferation, migration, invasion, and drug-resistance, underscoring the critical role of ECM alignment in promoting aggressive phenotypes. Leveraging the LC hydrogel model, we provided initial insights into the mechanisms underlying malignant progression via Western blot, reverse transcription-quantitative PCR and RNA sequencing analyses. Moreover, by implanting LC hydrogel precultured cancer cells into C57BL/6 mice, we established a tumor model exhibiting accelerated growth. Our findings demonstrate that the self-assembled peptide LC hydrogel can recapitulate tumor ECM alignment and enable the development of rapidly progressing tumor models for cancer research and drug screening.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124017"},"PeriodicalIF":12.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146045926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.biomaterials.2026.124010
Marc A. Fernández-Yagüe , Graham F. Barber , Aránzazu del Campo , Andrés J. García
Fibrotic capsule formation remains a major barrier in the clinical performance of biomedical implants. Here, we demonstrate that synthetic hydrogels mimicking the mechanical properties of fibrotic tissue trigger stromal cell activation and immune remodeling via focal adhesion kinase (FAK)-mediated mechanotransduction. Using a mechanically tunable poly(ethylene glycol) hydrogel platform and subcutaneous implantation in mice, we show that pharmacological inhibition of FAK activity significantly reduces α-smooth muscle actin (α-SMA)-positive myofibroblast activation, collagen I deposition, and fibrotic capsule thickness in a hydrogel stiffness-dependent manner. Flow cytometry and cytokine profiling revealed that FAK inhibition alters the fibrotic niche by reducing CD163-positive M2c macrophages and significantly downregulating pro-fibrotic cytokines including IL-6, and VEGF, while transiently increasing regulatory T cells and elevating IL-10 levels. Importantly, these changes occurred without parallel increases in canonical pro-inflammatory cytokines, indicating selective modulation rather than global immune suppression or activation. These findings position FAK as a central hub translating mechanical cues into coordinated stromal and immune responses. Targeting FAK mechanotransduction may provide a therapeutic strategy to mitigate foreign body responses and improve implant integration across regenerative applications.
{"title":"FAK modulates immune response and fibroblast activation in biomaterial-induced fibrosis","authors":"Marc A. Fernández-Yagüe , Graham F. Barber , Aránzazu del Campo , Andrés J. García","doi":"10.1016/j.biomaterials.2026.124010","DOIUrl":"10.1016/j.biomaterials.2026.124010","url":null,"abstract":"<div><div>Fibrotic capsule formation remains a major barrier in the clinical performance of biomedical implants. Here, we demonstrate that synthetic hydrogels mimicking the mechanical properties of fibrotic tissue trigger stromal cell activation and immune remodeling via focal adhesion kinase (FAK)-mediated mechanotransduction. Using a mechanically tunable poly(ethylene glycol) hydrogel platform and subcutaneous implantation in mice, we show that pharmacological inhibition of FAK activity significantly reduces α-smooth muscle actin (α-SMA)-positive myofibroblast activation, collagen I deposition, and fibrotic capsule thickness in a hydrogel stiffness-dependent manner. Flow cytometry and cytokine profiling revealed that FAK inhibition alters the fibrotic niche by reducing CD163-positive M2c macrophages and significantly downregulating pro-fibrotic cytokines including IL-6, and VEGF, while transiently increasing regulatory T cells and elevating IL-10 levels. Importantly, these changes occurred without parallel increases in canonical pro-inflammatory cytokines, indicating selective modulation rather than global immune suppression or activation. These findings position FAK as a central hub translating mechanical cues into coordinated stromal and immune responses. Targeting FAK mechanotransduction may provide a therapeutic strategy to mitigate foreign body responses and improve implant integration across regenerative applications.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124010"},"PeriodicalIF":12.9,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.biomaterials.2026.124015
Tiantian Sun , Qiushuang Zhang , Yicong Dai , Yuhan Liu , Xucong Teng , Jinghong Li
The metabolic differences between tumor cells and normal tissue cells offer potential targets for therapeutic intervention. For instance, compared to normal tissues, tumor cells exhibit a significantly higher dependency on methionine. However, current strategies for methionine restriction have limited clinical applicability due to systemic toxicity, poor patient compliance, and insufficient tumor targeting. In this study, we developed an engineered probiotic, Met-EcN, which is able to achieve targeted consumption of methionine within the tumor microenvironment. In the B16–F10 melanoma mouse model, the combination of Met-EcN and anti-PD-L1 antibody led to a 63 % increase in the tumor inhibition rate compared to anti-PD-L1 treatment alone, as well as a 50 % improvement in mouse survival rates. Additionally, this combination significantly enhanced T cell infiltration and activation. In the MC-38 colon cancer model, treatment with Met-EcN alongside anti-PD-L1 antibody inhibited tumor growth by 84.6 %, leading to complete regression of tumors in 80 % of the mice. The depletion of methionine levels by Met-EcN leads to a reduction in methylation levels within tumor cells, which facilitates the dissociation of cGAS protein from chromatin and activates the STING signaling pathway, thereby triggering an innate immune response. This study provides a novel therapeutic approach for overcoming tumor immune resistance.
{"title":"Methionine-depleting engineered probiotics promote PD-L1 antibody immunotherapy by activating the STING pathway","authors":"Tiantian Sun , Qiushuang Zhang , Yicong Dai , Yuhan Liu , Xucong Teng , Jinghong Li","doi":"10.1016/j.biomaterials.2026.124015","DOIUrl":"10.1016/j.biomaterials.2026.124015","url":null,"abstract":"<div><div>The metabolic differences between tumor cells and normal tissue cells offer potential targets for therapeutic intervention. For instance, compared to normal tissues, tumor cells exhibit a significantly higher dependency on methionine. However, current strategies for methionine restriction have limited clinical applicability due to systemic toxicity, poor patient compliance, and insufficient tumor targeting. In this study, we developed an engineered probiotic, Met-EcN, which is able to achieve targeted consumption of methionine within the tumor microenvironment. In the B16–F10 melanoma mouse model, the combination of Met-EcN and anti-PD-L1 antibody led to a 63 % increase in the tumor inhibition rate compared to anti-PD-L1 treatment alone, as well as a 50 % improvement in mouse survival rates. Additionally, this combination significantly enhanced T cell infiltration and activation. In the MC-38 colon cancer model, treatment with Met-EcN alongside anti-PD-L1 antibody inhibited tumor growth by 84.6 %, leading to complete regression of tumors in 80 % of the mice. The depletion of methionine levels by Met-EcN leads to a reduction in methylation levels within tumor cells, which facilitates the dissociation of cGAS protein from chromatin and activates the STING signaling pathway, thereby triggering an innate immune response. This study provides a novel therapeutic approach for overcoming tumor immune resistance.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124015"},"PeriodicalIF":12.9,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.biomaterials.2026.124014
Jiahong Ai , Yurong Zhang , Xingwei Li , Fangjun Huo , Caixia Yin
We developed an oral-to-urinalysis theranostic approach for inflammatory bowel disease (IBD) that aims to improve procedural practicality and safety by enabling diagnosis and treatment monitoring without invasive sampling. The strategy exploits disease-associated changes in intestinal chemistry that alter absorption, using the hydrophobicity shift between a fluorescent prodrug (MB-ASA) and its activated product methylene blue (MB). MB-ASA was synthesized by conjugating MB to 5-aminosalicylic acid (5-ASA), a first-line IBD therapy, via a ROS-responsive urea linkage. Owing to its high hydrophobicity, MB-ASA forms aggregates (hydrodynamic diameter ∼531 nm) that limit uptake by intestinal epithelial cells after oral administration in mice. In the inflamed IBD lumen, elevated reactive oxygen species cleave the urea bond, releasing hydrophilic MB and active 5-ASA. The liberated MB is then more readily absorbed and excreted, enabling IBD detection by monitoring fluorescence in the bladder and in excreted urine. Therapeutic activity was supported by histopathological comparisons before and after oral administration of MB-ASA, consistent with local activation and 5-ASA release. This work introduces a fluorescent prodrug platform that couples oral administration with urine-based fluorescence readouts to support theranostic assessment of IBD.
{"title":"An oral-to-urinalysis fluorescent prodrug platform for IBD theranostics","authors":"Jiahong Ai , Yurong Zhang , Xingwei Li , Fangjun Huo , Caixia Yin","doi":"10.1016/j.biomaterials.2026.124014","DOIUrl":"10.1016/j.biomaterials.2026.124014","url":null,"abstract":"<div><div>We developed an oral-to-urinalysis theranostic approach for inflammatory bowel disease (IBD) that aims to improve procedural practicality and safety by enabling diagnosis and treatment monitoring without invasive sampling. The strategy exploits disease-associated changes in intestinal chemistry that alter absorption, using the hydrophobicity shift between a fluorescent prodrug (<strong>MB-ASA</strong>) and its activated product methylene blue (MB). <strong>MB-ASA</strong> was synthesized by conjugating MB to 5-aminosalicylic acid (5-ASA), a first-line IBD therapy, <em>via</em> a ROS-responsive urea linkage. Owing to its high hydrophobicity, <strong>MB-ASA</strong> forms aggregates (hydrodynamic diameter ∼531 nm) that limit uptake by intestinal epithelial cells after oral administration in mice. In the inflamed IBD lumen, elevated reactive oxygen species cleave the urea bond, releasing hydrophilic MB and active 5-ASA. The liberated MB is then more readily absorbed and excreted, enabling IBD detection by monitoring fluorescence in the bladder and in excreted urine. Therapeutic activity was supported by histopathological comparisons before and after oral administration of <strong>MB-ASA</strong>, consistent with local activation and 5-ASA release. This work introduces a fluorescent prodrug platform that couples oral administration with urine-based fluorescence readouts to support theranostic assessment of IBD.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124014"},"PeriodicalIF":12.9,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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