Pub Date : 2026-04-01Epub Date: 2025-12-17DOI: 10.1016/j.bioactmat.2025.12.020
Tianyi Zhang , Yuhui Wu , Ye Tian , Youxiang Wang , Peng Zhang , Qiannuan Shi , Qun Fang , Jianzhang Pan , Qiao Jin , Jian Ji
Antimicrobial peptides (AMPs)-mimicking antimicrobial polymers show great potential as therapeutic alternatives to antibiotics in the looming “post-antibiotic era”. However, the discovery of new AMP-mimicking antimicrobial polymers is challenging due to the vast chemical space of side-chain combinations. The advancement of AI-guided high-throughput screening enables more efficient, precise, and intelligent material design. Herein, we integrate combinatorial chemistry, machine learning, and automated high-throughput synthesis and characterization platforms to establish a new paradigm for the design of antimicrobial polymers with excellent biocompatibility. Starting with a library of 13,728 combinations, a seed dataset of 400 structures is generated, followed by four Design-Build-Test-Learn iterations using a new machine learning model. 7 top-performing candidates are screened with a minimum inhibitory concentration (MIC) ≤ 8 μg/mL and an inhibitory concentration causing 20 % cell death (IC20) ≥ 64 μg/mL. The highest-performing polymer (MIC 2 μg/mL, IC20 256 μg/mL) shows similar in vivo therapeutic efficacy with ceftazidime. Overall, the integration of AI-guided high-throughput screening and combinatorial chemistry accelerates the discovery of new antimicrobial polymers, which provides a scalable strategy for developing novel antimicrobial agents.
{"title":"AI-guided precise design of antimicrobial polymers through high-throughput screening technology on an automated platform","authors":"Tianyi Zhang , Yuhui Wu , Ye Tian , Youxiang Wang , Peng Zhang , Qiannuan Shi , Qun Fang , Jianzhang Pan , Qiao Jin , Jian Ji","doi":"10.1016/j.bioactmat.2025.12.020","DOIUrl":"10.1016/j.bioactmat.2025.12.020","url":null,"abstract":"<div><div>Antimicrobial peptides (AMPs)-mimicking antimicrobial polymers show great potential as therapeutic alternatives to antibiotics in the looming “post-antibiotic era”. However, the discovery of new AMP-mimicking antimicrobial polymers is challenging due to the vast chemical space of side-chain combinations. The advancement of AI-guided high-throughput screening enables more efficient, precise, and intelligent material design. Herein, we integrate combinatorial chemistry, machine learning, and automated high-throughput synthesis and characterization platforms to establish a new paradigm for the design of antimicrobial polymers with excellent biocompatibility. Starting with a library of 13,728 combinations, a seed dataset of 400 structures is generated, followed by four Design-Build-Test-Learn iterations using a new machine learning model. 7 top-performing candidates are screened with a minimum inhibitory concentration (MIC) ≤ 8 μg/mL and an inhibitory concentration causing 20 % cell death (IC<sub>20</sub>) ≥ 64 μg/mL. The highest-performing polymer (MIC 2 μg/mL, IC<sub>20</sub> 256 μg/mL) shows similar in vivo therapeutic efficacy with ceftazidime. Overall, the integration of AI-guided high-throughput screening and combinatorial chemistry accelerates the discovery of new antimicrobial polymers, which provides a scalable strategy for developing novel antimicrobial agents.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 472-485"},"PeriodicalIF":18.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797593","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 : 2026-04-01Epub Date: 2025-12-18DOI: 10.1016/j.bioactmat.2025.11.041
Tianyu Yu , Xun Sun , Yang Liu , Yiming Dou , Ye Tian , Yiming Zhang , Genghao Wang , Lianyong Wang , Jianmin Han , Xiaohong Li , Xigao Cheng , Honglong Li , Haobo Pan , Lei Yang , Yanhong Zhao , Qiang Yang
Focal articular cartilage defects often progress to osteoarthritis, imposing a substantial global health burden. Current neglect of cartilage developmental regulation and cartilage microenvironment compromises therapeutic efficacy. We developed an innovation CE-SKP/CPH/P2G3 scaffold which effectively repairs focal cartilage defects and emulates native cartilage ontogeny: the superficial CE-SKP hydrogel layer recruits SMSCs and promotes chondrogenesis; the middle CPH hydrogel layer induces chondrocyte hypertrophic calcification, forming cartilage calcified layer; and the basal P2G3 nanofiber membrane isolates subchondral cells, enforcing a top-down developmental sequence and preserving a localized hypoxic niche. In vitro characterization confirms that the porosity, swelling ratio, biodegradation rate, and biocompatibility are optimal for sequential SMSC recruitment, cartilage differentiation, hypertrophic mineralization, and cells isolation. In vivo, the biomimetic tri-layer scaffold promotes regeneration of both cartilage and calcified cartilage by recapitulating the native ontogenetic progression from cartilage to calcified cartilage within the in vivo microenvironment, successfully restoring the normal physiological structure of articular cartilage by 24 weeks post-implantation. ScRNA-seq revealed SMSCs and a novel chondrocyte subpopulation CHON_5 as key repair populations, SMSCs mediated early repair via hypoxia response and migration, while CHON_5 promoted ECM remodeling, synergistically enhancing regeneration in late repair stage. Furthermore, we identified FGF signaling (FGF2-FGFR1/2 and FGF18-FGFR1/2 pairs) was crucial for MSC-CHON_5 communication during sequential cartilage regeneration. Overall, by recapitulating native developmental dynamics and microenvironmental cues, this scaffold offers a novel and effective strategy for functional cartilage regeneration and osteoarthritis treatment.
{"title":"Bioinspired scaffold recapitulating chondrogenic ontogeny and microenvironment for functional cartilage regeneration","authors":"Tianyu Yu , Xun Sun , Yang Liu , Yiming Dou , Ye Tian , Yiming Zhang , Genghao Wang , Lianyong Wang , Jianmin Han , Xiaohong Li , Xigao Cheng , Honglong Li , Haobo Pan , Lei Yang , Yanhong Zhao , Qiang Yang","doi":"10.1016/j.bioactmat.2025.11.041","DOIUrl":"10.1016/j.bioactmat.2025.11.041","url":null,"abstract":"<div><div>Focal articular cartilage defects often progress to osteoarthritis, imposing a substantial global health burden. Current neglect of cartilage developmental regulation and cartilage microenvironment compromises therapeutic efficacy. We developed an innovation CE-SKP/CPH/P2G3 scaffold which effectively repairs focal cartilage defects and emulates native cartilage ontogeny: the superficial CE-SKP hydrogel layer recruits SMSCs and promotes chondrogenesis; the middle CPH hydrogel layer induces chondrocyte hypertrophic calcification, forming cartilage calcified layer; and the basal P2G3 nanofiber membrane isolates subchondral cells, enforcing a top-down developmental sequence and preserving a localized hypoxic niche. <em>In vitro</em> characterization confirms that the porosity, swelling ratio, biodegradation rate, and biocompatibility are optimal for sequential SMSC recruitment, cartilage differentiation, hypertrophic mineralization, and cells isolation. <em>In vivo</em>, the biomimetic tri-layer scaffold promotes regeneration of both cartilage and calcified cartilage by recapitulating the native ontogenetic progression from cartilage to calcified cartilage within the <em>in vivo</em> microenvironment, successfully restoring the normal physiological structure of articular cartilage by 24 weeks post-implantation. ScRNA-seq revealed SMSCs and a novel chondrocyte subpopulation CHON_5 as key repair populations, SMSCs mediated early repair via hypoxia response and migration, while CHON_5 promoted ECM remodeling, synergistically enhancing regeneration in late repair stage. Furthermore, we identified FGF signaling (FGF2-FGFR1/2 and FGF18-FGFR1/2 pairs) was crucial for MSC-CHON_5 communication during sequential cartilage regeneration. Overall, by recapitulating native developmental dynamics and microenvironmental cues, this scaffold offers a novel and effective strategy for functional cartilage regeneration and osteoarthritis treatment.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 531-549"},"PeriodicalIF":18.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797597","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 : 2026-04-01Epub Date: 2025-12-13DOI: 10.1016/j.bioactmat.2025.12.001
Hao Xia , Qi Tang , Zhen Chen , Shujun Cao , Lihuang Wu , Lili Hao , Xiulan Hu , Lingyun Sun , Zhongwei Gu , Hongli Mao
Persistent inflammatory episodes driven by immune cell dysregulation pose a formidable clinical challenge in diabetic wound healing. Sustained and coordinated regulation of the immune niche within diabetic wounds is critical for tissue regeneration. Here, we develop a programmed therapeutic strategy based on arginine-lysine-methionine third-generation dendrimeric polypeptides whose dopamine-coated surfaces contain ferrous ions (G3D-Pmet25@PDA) to reprogram the immune niche. G3D-Pmet25@PDA exhibits a core–shell structure: ferrous ions on the surface are rapidly released under near-infrared (NIR) laser irradiation, while methionine chains encapsulated within the dopamine shell undergo a reactive oxygen species (ROS) triggered hydrophilic transition that liberates arginine for cascade release. Under NIR laser irradiation, G3D-Pmet25@PDA initiates a clearance program targeting dysregulated immune cells and concurrently reprograms the energy metabolism of newly recruited immune cells, thereby reshaping the immune niche to alleviate inflammation and activate tissue-regenerative programs for accelerated healing. Moreover, sustained low-dose nitric oxide release caused by arginine accelerates angiogenesis, which is beneficial for tissue regeneration. These findings expand the perspective on the intricate coordination of the immune system in diabetic wound repair and reveal new strategies for novel immunomodulatory biomaterials.
{"title":"Engineered polypeptide cascade-release platform restores macrophage plasticity for accelerated diabetic wound healing","authors":"Hao Xia , Qi Tang , Zhen Chen , Shujun Cao , Lihuang Wu , Lili Hao , Xiulan Hu , Lingyun Sun , Zhongwei Gu , Hongli Mao","doi":"10.1016/j.bioactmat.2025.12.001","DOIUrl":"10.1016/j.bioactmat.2025.12.001","url":null,"abstract":"<div><div>Persistent inflammatory episodes driven by immune cell dysregulation pose a formidable clinical challenge in diabetic wound healing. Sustained and coordinated regulation of the immune niche within diabetic wounds is critical for tissue regeneration. Here, we develop a programmed therapeutic strategy based on arginine-lysine-methionine third-generation dendrimeric polypeptides whose dopamine-coated surfaces contain ferrous ions (G3D-Pmet<sub>25</sub>@PDA) to reprogram the immune niche. G3D-Pmet<sub>25</sub>@PDA exhibits a core–shell structure: ferrous ions on the surface are rapidly released under near-infrared (NIR) laser irradiation, while methionine chains encapsulated within the dopamine shell undergo a reactive oxygen species (ROS) triggered hydrophilic transition that liberates arginine for cascade release. Under NIR laser irradiation, G3D-Pmet<sub>25</sub>@PDA initiates a clearance program targeting dysregulated immune cells and concurrently reprograms the energy metabolism of newly recruited immune cells, thereby reshaping the immune niche to alleviate inflammation and activate tissue-regenerative programs for accelerated healing. Moreover, sustained low-dose nitric oxide release caused by arginine accelerates angiogenesis, which is beneficial for tissue regeneration. These findings expand the perspective on the intricate coordination of the immune system in diabetic wound repair and reveal new strategies for novel immunomodulatory biomaterials.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 370-387"},"PeriodicalIF":18.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748144","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 : 2026-04-01Epub Date: 2025-12-12DOI: 10.1016/j.bioactmat.2025.12.005
Yisi Liu , Jie Hu , Yu Qian , Qian Wu , Yan Su , Hao Jiang , Hui He , Qianglong Chen , Qifan Yu , Qiang Yang , Ting Liang , Caihong Zhu , Zhangqin Yuan , Houfeng Zheng , Fengxuan Han , Bin Li
Low back pain affects 70–85 % of adults globally, with intervertebral disc degeneration (IVDD) driving nearly half of cases. Integrating human genetic evidence from a large-scale genome-wide association study in up to 829,699 participants along with immunofluorescence staining of nucleus pulposus in patients with varying degrees of IVDD, we identified PI3K-Akt signaling as a central pathway in lumbar disc herniation. Guided by this genetic blueprint, we engineered a piezoelectric scaffold GelMA-FF (GF) which can transform physiological loading into regenerative bioelectrical signals, and regulate PI3K-Akt pathway. The GF system synergizes gelatin methacryloyl's biomechanical compatibility with diphenylalanine crystals' piezoelectric capacity, directly targeting fixed charge density restoration—the electrophysiological hallmark of IVDD. The results reveal that GF-generated electrical signals could change the pathogenic PI3K-Akt/NF-κB axis, shifting disc metabolism from inflammatory catabolism to anabolic regeneration. This GF system also enhances mitochondrial energetics and extracellular matrix synthesis, achieving structural and functional recovery in preclinical models. This study proposes a novel strategy—a paradigm where genetic risk architectures guide physiology-matched biomaterials to transduce endogenous mechanical microenvironment cues into regeneration signals.
{"title":"Harnessing piezoelectric stimulation to modulate PI3K-AKT signaling for intervertebral disc regeneration","authors":"Yisi Liu , Jie Hu , Yu Qian , Qian Wu , Yan Su , Hao Jiang , Hui He , Qianglong Chen , Qifan Yu , Qiang Yang , Ting Liang , Caihong Zhu , Zhangqin Yuan , Houfeng Zheng , Fengxuan Han , Bin Li","doi":"10.1016/j.bioactmat.2025.12.005","DOIUrl":"10.1016/j.bioactmat.2025.12.005","url":null,"abstract":"<div><div>Low back pain affects 70–85 % of adults globally, with intervertebral disc degeneration (IVDD) driving nearly half of cases. Integrating human genetic evidence from a large-scale genome-wide association study in up to 829,699 participants along with immunofluorescence staining of nucleus pulposus in patients with varying degrees of IVDD, we identified PI3K-Akt signaling as a central pathway in lumbar disc herniation. Guided by this genetic blueprint, we engineered a piezoelectric scaffold GelMA-FF (GF) which can transform physiological loading into regenerative bioelectrical signals, and regulate PI3K-Akt pathway. The GF system synergizes gelatin methacryloyl's biomechanical compatibility with diphenylalanine crystals' piezoelectric capacity, directly targeting fixed charge density restoration—the electrophysiological hallmark of IVDD. The results reveal that GF-generated electrical signals could change the pathogenic PI3K-Akt/NF-κB axis, shifting disc metabolism from inflammatory catabolism to anabolic regeneration. This GF system also enhances mitochondrial energetics and extracellular matrix synthesis, achieving structural and functional recovery in preclinical models. This study proposes a novel strategy—a paradigm where genetic risk architectures guide physiology-matched biomaterials to transduce endogenous mechanical microenvironment cues into regeneration signals.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 283-302"},"PeriodicalIF":18.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748622","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 : 2026-04-01Epub Date: 2025-12-11DOI: 10.1016/j.bioactmat.2025.12.012
Yinghao Li , Liang Yao , Jiahao Liu , Yi Situ , Chunyu Zhao , Tianyu Mao , Xi Wang , Rijian Song , Hongyun Tai , Zhonglei He , Jing Lyu , Wenxin Wang
Cationic modification of hyaluronic acid (HA) is challenging due to its polyanionic nature, poor reactivity in water, and the instability of conventional coupling intermediates. This limits the development of HA-based components in non-viral gene delivery systems, which already suffer from amorphous morphology and mechanical fragility that reduce their transfection efficiency. Here, we reprogram a classically unfavorable EDAC-mediated rearrangement into a productive synthetic route, enabling direct cationization of hyaluronic acid (HA) through spontaneous O-acylisourea rearrangement. This water-based, catalyst-free process achieves up to 70 % substitution of HA's carboxyl groups—introducing cationic tertiary amine functionalities in water. The resulting aminated-hyaluronic acid (HAA) scaffolds act as rigid structural backbones in virus-inspired polymer–DNA nanoparticles termed as “Skeletoplexes”, with enhanced stability and performance. When incorporated into polyplexes formed from diverse cationic systems—including poly(β-amino esters) and commercial vectors such as BrPERfect, Xfect, jetPEI, and Lipofectamine3000—HAA scaffolds improved in vitro transfection efficiency by up to 4-fold and in vivo gene expression by approximately 2-fold. These results establish a generalizable and green scaffold-based strategy that bridges the structural and functional gap between viral and non-viral gene delivery vectors.
{"title":"EDAC-mediated O-acylisourea rearrangement for tertiary amine cationization of hyaluronic acid (HA) and its application as structural backbones in virus-inspired polyplexes","authors":"Yinghao Li , Liang Yao , Jiahao Liu , Yi Situ , Chunyu Zhao , Tianyu Mao , Xi Wang , Rijian Song , Hongyun Tai , Zhonglei He , Jing Lyu , Wenxin Wang","doi":"10.1016/j.bioactmat.2025.12.012","DOIUrl":"10.1016/j.bioactmat.2025.12.012","url":null,"abstract":"<div><div>Cationic modification of hyaluronic acid (HA) is challenging due to its polyanionic nature, poor reactivity in water, and the instability of conventional coupling intermediates. This limits the development of HA-based components in non-viral gene delivery systems, which already suffer from amorphous morphology and mechanical fragility that reduce their transfection efficiency. Here, we reprogram a classically unfavorable EDAC-mediated rearrangement into a productive synthetic route, enabling direct cationization of hyaluronic acid (HA) through spontaneous O-acylisourea rearrangement. This water-based, catalyst-free process achieves up to 70 % substitution of HA's carboxyl groups—introducing cationic tertiary amine functionalities in water. The resulting aminated-hyaluronic acid (HAA) scaffolds act as rigid structural backbones in virus-inspired polymer–DNA nanoparticles termed as “Skeletoplexes”, with enhanced stability and performance. When incorporated into polyplexes formed from diverse cationic systems—including poly(β-amino esters) and commercial vectors such as BrPERfect, Xfect, jetPEI, and Lipofectamine3000—HAA scaffolds improved <em>in vitro</em> transfection efficiency by up to 4-fold and <em>in vivo</em> gene expression by approximately 2-fold. These results establish a generalizable and green scaffold-based strategy that bridges the structural and functional gap between viral and non-viral gene delivery vectors.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 274-282"},"PeriodicalIF":18.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748567","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 : 2026-04-01Epub Date: 2025-12-13DOI: 10.1016/j.bioactmat.2025.11.040
Shuyu Wen , Junwei Zhang , Ying Zhou , Jinchi Zhang , Chao Zhang , Chunli Wang , Yixuan Wang , Zongtao Liu , Yin Xu , Bohao Jian , Hong Cao , Shijie Wang , Xing Liu , Yunlong Wu , Jiawei Shi , Fei Li , Kang Xu , Weihua Qiao , Nianguo Dong
Calcification remains a major barrier to the long-term durability of bioprosthetic heart valves (BHVs), yet effective therapeutic strategies are still lacking. Emerging evidence suggests that targeting the immune response holds strong promise for mitigating BHV calcification, although the precise mechanisms remain elusive. Here, we integrated single-cell RNA sequencing, spatial transcriptomics, and multiple experimental models to elucidate the immunological mechanisms of BHV calcification and to develop targeted immunomodulatory strategies for anti-calcification therapy. The first spatiotemporal cell atlas of BHV calcification highlights macrophages as key immune drivers, confirmed by various immunodeficient mouse models. Notably, we identified a novel pro-calcification macrophage subset characterized by low Acod1 expression and reduced itaconate production. In macrophage-specific Acod1 knockout models, increased apoptosis, oxidative stress, and extracellular matrix disruption via the HIF-1α–glycolysis pathway accelerated calcification, which was reversed by itaconate supplementation. Guided by these findings, we designed two biomaterial-based therapeutic strategies: a BHV surface functionalized with itaconate via layer-by-layer assembly for localized, sustained release; and tetrazine-functionalized nanoparticles encapsulating itaconate, selectively delivered to trans-cyclooctene–modified BHVs through a bioorthogonal click reaction. Both platforms exhibited favorable biocompatibility and effectively attenuated BHV calcification in vivo, demonstrating strong translational potential. Together, our findings underscore the immune-metabolic axis underlying BHV calcification and pave the way for advanced immune-modulating treatments in BHV management.
{"title":"Dual itaconate delivery systems modulate macrophage Acod1-Hif-1α-glycolysis axis for immunotherapy of bioprosthetic heart valve calcification","authors":"Shuyu Wen , Junwei Zhang , Ying Zhou , Jinchi Zhang , Chao Zhang , Chunli Wang , Yixuan Wang , Zongtao Liu , Yin Xu , Bohao Jian , Hong Cao , Shijie Wang , Xing Liu , Yunlong Wu , Jiawei Shi , Fei Li , Kang Xu , Weihua Qiao , Nianguo Dong","doi":"10.1016/j.bioactmat.2025.11.040","DOIUrl":"10.1016/j.bioactmat.2025.11.040","url":null,"abstract":"<div><div>Calcification remains a major barrier to the long-term durability of bioprosthetic heart valves (BHVs), yet effective therapeutic strategies are still lacking. Emerging evidence suggests that targeting the immune response holds strong promise for mitigating BHV calcification, although the precise mechanisms remain elusive. Here, we integrated single-cell RNA sequencing, spatial transcriptomics, and multiple experimental models to elucidate the immunological mechanisms of BHV calcification and to develop targeted immunomodulatory strategies for anti-calcification therapy. The first spatiotemporal cell atlas of BHV calcification highlights macrophages as key immune drivers, confirmed by various immunodeficient mouse models. Notably, we identified a novel pro-calcification macrophage subset characterized by low Acod1 expression and reduced itaconate production. In macrophage-specific Acod1 knockout models, increased apoptosis, oxidative stress, and extracellular matrix disruption via the HIF-1α–glycolysis pathway accelerated calcification, which was reversed by itaconate supplementation. Guided by these findings, we designed two biomaterial-based therapeutic strategies: a BHV surface functionalized with itaconate via layer-by-layer assembly for localized, sustained release; and tetrazine-functionalized nanoparticles encapsulating itaconate, selectively delivered to trans-cyclooctene–modified BHVs through a bioorthogonal click reaction. Both platforms exhibited favorable biocompatibility and effectively attenuated BHV calcification in vivo, demonstrating strong translational potential. Together, our findings underscore the immune-metabolic axis underlying BHV calcification and pave the way for advanced immune-modulating treatments in BHV management.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 388-407"},"PeriodicalIF":18.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797542","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 : 2026-04-01Epub Date: 2025-12-17DOI: 10.1016/j.bioactmat.2025.11.038
Peng Wang , Haiyue Zhao , Shuo Zhang , Yuhui Guo , Xin Xing , Shuai Zhou , Shuai Yang , Fengkun Wang , Wei Chen , Juan Wang , Yingze Zhang
The accumulation of senescent chondrocytes contributes significantly to osteoarthritis (OA) progression, establishing a self-perpetuating cycle of cartilage deterioration. Current therapeutic strategies remain limited by inadequate precision to target senescent populations and the inability to simultaneously trigger endogenous regenerative processes. Herein, we developed a hydrogel microsphere system to locally eliminate senescent chondrocytes, thereby creating a permissive microenvironment and facilitating endogenous stem cell recruitment to accelerate cartilage repair. Specifically, chondrocyte membranes (CM) overexpressing natural killer group 2 member D (NKG2D) receptors (NCM) were fabricated via plasmid transfection and extrusion to target upregulated NKG2D ligands on senescent cells. The fusion of ABT263-loaded liposomes (A-lipo) with NCM produced the senolytic ANCM nanoparticles. Subsequently, ANCM and SDF-1α were co-encapsulated into methacrylic anhydride (MA)-modified hyaluronic acid (HA) hydrogel microspheres (SHM) using microfluidics. The resulting ANCM@SHM exhibited remarkable biocompatibility and a dual-phase functionality: hydrogel-enhanced articular retention followed by ANCM-mediated active targeting of senescent chondrocytes. Functional assessments validated the effective clearance of senescent chondrocytes, achieved by inducing mitochondrial outer membrane permeabilization (MOMP), was accompanied by metabolic reprogramming of surviving chondrocytes toward an anabolic phenotype. Simultaneously, sustained SDF-1α release induced robust mesenchymal stromal cells (MSCs) homing and chondrogenic differentiation, resulting in synergistic cartilage remodeling. In vivo evaluations demonstrated a pronounced attenuation of OA progression, attributable to synergistic remodeling of the joint microenvironment. This multidimensional engineering strategy disrupts the vicious cycle of senescence-associated cartilage degeneration by integrating targeted senolysis with stem cell-mediated regeneration, providing a promising therapeutic approach for OA management.
{"title":"Injectable microgels carrying engineered biomimetic nanoparticles for osteoarthritis therapy via dual-targeted senescent chondrocyte clearance and endogenous repair promotion","authors":"Peng Wang , Haiyue Zhao , Shuo Zhang , Yuhui Guo , Xin Xing , Shuai Zhou , Shuai Yang , Fengkun Wang , Wei Chen , Juan Wang , Yingze Zhang","doi":"10.1016/j.bioactmat.2025.11.038","DOIUrl":"10.1016/j.bioactmat.2025.11.038","url":null,"abstract":"<div><div>The accumulation of senescent chondrocytes contributes significantly to osteoarthritis (OA) progression, establishing a self-perpetuating cycle of cartilage deterioration. Current therapeutic strategies remain limited by inadequate precision to target senescent populations and the inability to simultaneously trigger endogenous regenerative processes. Herein, we developed a hydrogel microsphere system to locally eliminate senescent chondrocytes, thereby creating a permissive microenvironment and facilitating endogenous stem cell recruitment to accelerate cartilage repair. Specifically, chondrocyte membranes (CM) overexpressing natural killer group 2 member D (NKG2D) receptors (NCM) were fabricated via plasmid transfection and extrusion to target upregulated NKG2D ligands on senescent cells. The fusion of ABT263-loaded liposomes (A-lipo) with NCM produced the senolytic ANCM nanoparticles. Subsequently, ANCM and SDF-1α were co-encapsulated into methacrylic anhydride (MA)-modified hyaluronic acid (HA) hydrogel microspheres (SHM) using microfluidics. The resulting ANCM@SHM exhibited remarkable biocompatibility and a dual-phase functionality: hydrogel-enhanced articular retention followed by ANCM-mediated active targeting of senescent chondrocytes. Functional assessments validated the effective clearance of senescent chondrocytes, achieved by inducing mitochondrial outer membrane permeabilization (MOMP), was accompanied by metabolic reprogramming of surviving chondrocytes toward an anabolic phenotype. Simultaneously, sustained SDF-1α release induced robust mesenchymal stromal cells (MSCs) homing and chondrogenic differentiation, resulting in synergistic cartilage remodeling. <em>In vivo</em> evaluations demonstrated a pronounced attenuation of OA progression, attributable to synergistic remodeling of the joint microenvironment. This multidimensional engineering strategy disrupts the vicious cycle of senescence-associated cartilage degeneration by integrating targeted senolysis with stem cell-mediated regeneration, providing a promising therapeutic approach for OA management.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 486-504"},"PeriodicalIF":18.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797592","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 : 2026-04-01Epub Date: 2025-12-02DOI: 10.1016/j.bioactmat.2025.11.003
Manxiang Wu , Dong Xie , Lianfu Wang , Zhusheng Liu , Hongying Bao , Tao Ye , Chengyuan Hong , Jie Lin , Tianxiang Chen , Aiguo Wu , Qiang Li
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Its pathogenesis involves aberrant activation and aggressive proliferation of fibroblast-like synoviocytes (FLS), excessive macrophage infiltration, and disrupted M1/M2 macrophage polarization within the synovial microenvironment (SME). However, current therapies remain inadequate for precise SME modulation, often leading to limited efficacy and poor prognosis. To address this challenge, we developed a multifunctional nanocapsule, termed RP/HP@Mn/L, which is composed of a low molecular weight heparin (LMWH)-modified, Mn2+-doped hollow mesoporous polydopamine (HP) nanocarrier co-loaded with rapamycin (Rap) and paeoniflorin (Pae). This nanocapsule's dual-ligand strategy targets P-selectin on inflamed endothelial cells and integrin αM on inflammatory macrophages, enabling precise spatiotemporal accumulation at the pathological site. This nanocapsule enables spatiotemporally specific targeting of both inflammatory endothelial cells and inflammatory macrophages, thereby enhancing precise drug delivery to pathological sites. Mechanistic investigations revealed that RP/HP@Mn/L, in combination with mild photothermal therapy (PTT) mediated by HP, effectively suppressed FLS proliferation and invasion. Concurrently, it promoted the polarization of macrophages from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. These synergistic effects facilitated the remodeling of the SME, thereby alleviating synovitis and enhancing bone repair in RA. In conclusion, this study proposes a spatiotemporally targeted combinatorial nanotherapeutic strategy that integrates multimodal mechanisms for SME modulation. This approach represents a promising therapeutic platform for improving outcomes in RA and other autoimmune disorders.
{"title":"Spatiotemporally targeted nanocapsules combined with mild photothermal therapy regulate the synovial microenvironment in rheumatoid arthritis","authors":"Manxiang Wu , Dong Xie , Lianfu Wang , Zhusheng Liu , Hongying Bao , Tao Ye , Chengyuan Hong , Jie Lin , Tianxiang Chen , Aiguo Wu , Qiang Li","doi":"10.1016/j.bioactmat.2025.11.003","DOIUrl":"10.1016/j.bioactmat.2025.11.003","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Its pathogenesis involves aberrant activation and aggressive proliferation of fibroblast-like synoviocytes (FLS), excessive macrophage infiltration, and disrupted M1/M2 macrophage polarization within the synovial microenvironment (SME). However, current therapies remain inadequate for precise SME modulation, often leading to limited efficacy and poor prognosis. To address this challenge, we developed a multifunctional nanocapsule, termed RP/HP@Mn/L, which is composed of a low molecular weight heparin (LMWH)-modified, Mn<sup>2+</sup>-doped hollow mesoporous polydopamine (HP) nanocarrier co-loaded with rapamycin (Rap) and paeoniflorin (Pae). This nanocapsule's dual-ligand strategy targets P-selectin on inflamed endothelial cells and integrin αM on inflammatory macrophages, enabling precise spatiotemporal accumulation at the pathological site. This nanocapsule enables spatiotemporally specific targeting of both inflammatory endothelial cells and inflammatory macrophages, thereby enhancing precise drug delivery to pathological sites. Mechanistic investigations revealed that RP/HP@Mn/L, in combination with mild photothermal therapy (PTT) mediated by HP, effectively suppressed FLS proliferation and invasion. Concurrently, it promoted the polarization of macrophages from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. These synergistic effects facilitated the remodeling of the SME, thereby alleviating synovitis and enhancing bone repair in RA. In conclusion, this study proposes a spatiotemporally targeted combinatorial nanotherapeutic strategy that integrates multimodal mechanisms for SME modulation. This approach represents a promising therapeutic platform for improving outcomes in RA and other autoimmune disorders.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 33-48"},"PeriodicalIF":18.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145692033","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}
The Tantalum-Titanium (TaTi) alloys demonstrate significant potential as an orthopedic implant material. This study presents the development and comprehensive evaluation of novel additive manufactured TaTi alloys for orthopedic implant applications. Through a combination of materials engineering and biological validation, we designed pre-alloyed TaTi spherical powders with varying compositions (Ta25, Ta55, and Ta75) and fabricated dense and porous structures via selective laser melting (SLM). The SLM Ta55 alloy (Ti-55 wt %Ta) exhibited optimal mechanical properties, including a tensile strength of 891 MPa and an elastic modulus of 74 GPa, closely matching cortical bone. Surface characterization revealed that oxide layer (comprising Ta2O5/TiO2) of SLM Ta55 promoted osteoblast adhesion and focal adhesion signaling activation. In vitro studies demonstrated superior osteogenic differentiation of MC3T3-E1 cells on SLM Ta55, evidenced by upregulated alkaline phosphatase (ALP) activity, mineralization, and osteogenic gene expression (ALP, Col-1, OCN, OPN). Transcriptomic analysis linked these effects to enhanced extracellular matrix remodeling and integrin-mediated mechanotransduction. Immunomodulatory assessments showed SLM Ta55 facilitated M2 macrophage polarization by suppressing JAK-STAT1 and TNF/NF-κB pro-inflammatory pathways while activating JAK3/STAT6, creating an anti-inflammatory microenvironment conducive to bone regeneration. In vivo rabbit femoral defect models confirmed SLM Ta55's exceptional osseointegration, with 37 % new bone area at 12 weeks, outperforming pure Ti and other TaTi alloys. Histological and immunofluorescence analyses validated reduced inflammation and increased osteocalcin expression around SLM Ta55 implants. This work establishes SLM Ta55 as a promising next-generation orthopedic biomaterial, synergizing mechanical compatibility, osteogenesis, and immunomodulation to advance personalized bone repair strategies.
{"title":"Additively manufactured Tantalum-titanium alloys with optimized osteogenic and immunomodulatory properties for load-bearing orthopedic implants","authors":"Junlei Li , Fang Cao , Xiaoyan Chen , Yada Li, Guangxiao Yin, Pinqiao Yi, Liqun Song, Jiahui Yang, Zhihua Cheng, Jiawei Ying, Liangliang Cheng, Simiao Tian, Xiuzhi Zhang, Dewei Zhao","doi":"10.1016/j.bioactmat.2025.11.029","DOIUrl":"10.1016/j.bioactmat.2025.11.029","url":null,"abstract":"<div><div>The Tantalum-Titanium (TaTi) alloys demonstrate significant potential as an orthopedic implant material. This study presents the development and comprehensive evaluation of novel additive manufactured TaTi alloys for orthopedic implant applications. Through a combination of materials engineering and biological validation, we designed pre-alloyed TaTi spherical powders with varying compositions (Ta25, Ta55, and Ta75) and fabricated dense and porous structures via selective laser melting (SLM). The SLM Ta55 alloy (Ti-55 wt %Ta) exhibited optimal mechanical properties, including a tensile strength of 891 MPa and an elastic modulus of 74 GPa, closely matching cortical bone. Surface characterization revealed that oxide layer (comprising Ta<sub>2</sub>O<sub>5</sub>/TiO<sub>2</sub>) of SLM Ta55 promoted osteoblast adhesion and focal adhesion signaling activation. In vitro studies demonstrated superior osteogenic differentiation of MC3T3-E1 cells on SLM Ta55, evidenced by upregulated alkaline phosphatase (ALP) activity, mineralization, and osteogenic gene expression (ALP, Col-1, OCN, OPN). Transcriptomic analysis linked these effects to enhanced extracellular matrix remodeling and integrin-mediated mechanotransduction. Immunomodulatory assessments showed SLM Ta55 facilitated M2 macrophage polarization by suppressing JAK-STAT1 and TNF/NF-κB pro-inflammatory pathways while activating JAK3/STAT6, creating an anti-inflammatory microenvironment conducive to bone regeneration. In vivo rabbit femoral defect models confirmed SLM Ta55's exceptional osseointegration, with 37 % new bone area at 12 weeks, outperforming pure Ti and other TaTi alloys. Histological and immunofluorescence analyses validated reduced inflammation and increased osteocalcin expression around SLM Ta55 implants. This work establishes SLM Ta55 as a promising next-generation orthopedic biomaterial, synergizing mechanical compatibility, osteogenesis, and immunomodulation to advance personalized bone repair strategies.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 49-69"},"PeriodicalIF":18.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145692034","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 : 2026-04-01Epub Date: 2025-12-13DOI: 10.1016/j.bioactmat.2025.12.002
Kaize Su , Yingda Yan , Jun Huang , Yini Chen , Xiangcun Shang , Xiaoying Wang , Yixiong Liu , Zefeng Lai , Fangming Song , Zhiyong Zhang , Panpan Wu , Keke Wu , Xing-Jie Liang
The therapy of chronic periodontitis poses a perennial challenge due to its intricate etiology, specific bacterial involvement, and the presence of an inflammatory immune microenvironment. The misuse of antibiotics not only triggers bacterial resistance but also disrupts the balance of oral microbiota, exacerbating the host's inflammatory response. Herein, a novel integrated synergistic hydrogel delivery platform (named GM/OHA-GZN&M) was designed to facilitate rapid, non-invasive, and antibiotic-free periodontitis treatment. This injectable hydrogel delivery platform fulfils three distinct roles: as a subgingival plaque disruptor, immune microenvironment remodeler, and microbiome modulator. As a subgingival plaque disruptor, GM/OHA-GZN&M hydrogel effectively disrupted bacterial membrane homeostasis, depolarized it, and induced the leakage of materials in the membrane. As an immune microenvironment remodeler, it effectively mediates the targeted clearance of mitochondrial reactive oxygen species (mtROS) through polyphenols, restores mitochondrial function, and disrupts the free radical cycle of inflammation. As a microbiome modulator, it effectively suppressed pathogenic bacterial overgrowth, restored oral gingival microbiota balance in rats, and created a favorable subgingival microenvironment for periodontitis treatment. In in vivo experiments, the GM/OHA-GZN&M hydrogel was used to treat a periodontitis model established by silk thread ligation in rats. Histological, microbiological, and biochemical analyses demonstrated that the hydrogel could significantly suppress inflammation and effectively promote alveolar bone regeneration through immunomodulation. To sum up, this study presents a supports therapeutic potential approach for managing periodontitis.
{"title":"Mitochondrial-targeted injectable hydrogel for periodontitis therapy via oral immunity and flora regulation","authors":"Kaize Su , Yingda Yan , Jun Huang , Yini Chen , Xiangcun Shang , Xiaoying Wang , Yixiong Liu , Zefeng Lai , Fangming Song , Zhiyong Zhang , Panpan Wu , Keke Wu , Xing-Jie Liang","doi":"10.1016/j.bioactmat.2025.12.002","DOIUrl":"10.1016/j.bioactmat.2025.12.002","url":null,"abstract":"<div><div>The therapy of chronic periodontitis poses a perennial challenge due to its intricate etiology, specific bacterial involvement, and the presence of an inflammatory immune microenvironment. The misuse of antibiotics not only triggers bacterial resistance but also disrupts the balance of oral microbiota, exacerbating the host's inflammatory response. Herein, a novel integrated synergistic hydrogel delivery platform (named GM/OHA-GZN&M) was designed to facilitate rapid, non-invasive, and antibiotic-free periodontitis treatment. This injectable hydrogel delivery platform fulfils three distinct roles: as a subgingival plaque disruptor, immune microenvironment remodeler, and microbiome modulator. As a subgingival plaque disruptor, GM/OHA-GZN&M hydrogel effectively disrupted bacterial membrane homeostasis, depolarized it, and induced the leakage of materials in the membrane. As an immune microenvironment remodeler, it effectively mediates the targeted clearance of mitochondrial reactive oxygen species (mtROS) through polyphenols, restores mitochondrial function, and disrupts the free radical cycle of inflammation. As a microbiome modulator, it effectively suppressed pathogenic bacterial overgrowth, restored oral gingival microbiota balance in rats, and created a favorable subgingival microenvironment for periodontitis treatment. In <em>in vivo</em> experiments, the GM/OHA-GZN&M hydrogel was used to treat a periodontitis model established by silk thread ligation in rats. Histological, microbiological, and biochemical analyses demonstrated that the hydrogel could significantly suppress inflammation and effectively promote alveolar bone regeneration through immunomodulation. To sum up, this study presents a supports therapeutic potential approach for managing periodontitis.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 348-369"},"PeriodicalIF":18.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748147","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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