Pub 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":"2025-12-17","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 : 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":"2025-12-17","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 : 2025-12-16DOI: 10.1016/j.bioactmat.2025.12.019
Ashkan Bigham , Anna Mariano , Aldo R. Boccaccini , Luigi Ambrosio , Maria Grazia Raucci
Black phosphorus (BP) has attracted considerable attention as a biodegradable, stimuli-responsive 2D nanomaterial, emerging as a powerful theragenerative platform that integrates disease modulation with tissue regeneration. While earlier studies focused mainly on its anticancer properties, this review provides the first comprehensive analysis of BP as a theragenerative agent, unifying its disease-modulating capacity with its ability to stimulate tissue regeneration across multiple organs. BP exhibits several shared advantages: its degradation releases bioactive phosphate ions that support tissue repair; its highly reactive surface promotes cell interactions and enables efficient drug loading and delivery; its responsiveness to external stimuli, such as Near-infrared (NIR) light, ultrasound, and electrical signals, allows precise, on-demand therapeutic activation; and its ability to modulate reactive oxygen species (ROS) and immune modulation helps balance inflammation and regeneration. These properties collectively enhance osteogenesis and implant integration in bone, accelerate wound healing in skin, promote neural repair and redox homeostasis, protect cardiac tissue, and support recovery in kidney and liver injuries. By highlighting these mechanisms, this review emphasizes BP's versatility as a multifunctional nanomaterial capable of addressing pathological conditions while simultaneously stimulating endogenous regenerative pathways, thereby laying the foundation for its translation into next-generation theragenerative platforms.
{"title":"Black phosphorus in theragenerative medicine: a multi-organ perspective on disease modulation and tissue repair","authors":"Ashkan Bigham , Anna Mariano , Aldo R. Boccaccini , Luigi Ambrosio , Maria Grazia Raucci","doi":"10.1016/j.bioactmat.2025.12.019","DOIUrl":"10.1016/j.bioactmat.2025.12.019","url":null,"abstract":"<div><div>Black phosphorus (BP) has attracted considerable attention as a biodegradable, stimuli-responsive 2D nanomaterial, emerging as a powerful theragenerative platform that integrates disease modulation with tissue regeneration. While earlier studies focused mainly on its anticancer properties, this review provides the first comprehensive analysis of BP as a theragenerative agent, unifying its disease-modulating capacity with its ability to stimulate tissue regeneration across multiple organs. BP exhibits several shared advantages: its degradation releases bioactive phosphate ions that support tissue repair; its highly reactive surface promotes cell interactions and enables efficient drug loading and delivery; its responsiveness to external stimuli, such as Near-infrared (NIR) light, ultrasound, and electrical signals, allows precise, on-demand therapeutic activation; and its ability to modulate reactive oxygen species (ROS) and immune modulation helps balance inflammation and regeneration. These properties collectively enhance osteogenesis and implant integration in bone, accelerate wound healing in skin, promote neural repair and redox homeostasis, protect cardiac tissue, and support recovery in kidney and liver injuries. By highlighting these mechanisms, this review emphasizes BP's versatility as a multifunctional nanomaterial capable of addressing pathological conditions while simultaneously stimulating endogenous regenerative pathways, thereby laying the foundation for its translation into next-generation theragenerative platforms.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 422-471"},"PeriodicalIF":18.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797594","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 : 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":"2025-12-13","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 : 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":"2025-12-13","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}
Pub 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":"2025-12-13","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 : 2025-12-13DOI: 10.1016/j.bioactmat.2025.12.016
Yaqi Zhang , Zeyuan Jin , Lvwan Xu , Zilong Zhong , Xinyu Wang , Changyou Gao , Lanjuan Li
Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI) and acute liver failure (ALF) worldwide, representing a major clinical and public health challenge due to its rapid onset and high morbidity. Current clinical treatment is limited to N-acetylcysteine (NAC), but its efficacy is highly time-dependent and the prolonged regimen imposes additional clinical burdens and side effects. Natural compounds hold tremendous promise for hepatoprotection, but their clinical translation is limited by unfavorable physicochemical and pharmacokinetic properties. In this study, tectorigenin (Tec), an isoflavone possessing anti-inflammatory and antioxidative activity, was encapsulated within a reactive oxygen species (ROS)-responsive nanoplatform (PBHB@Tec) to enhance bioavailability and enable site-selective hepatoprotection. PBHB@Tec possessed diameters compatible with passage through hepatic sinusoidal fenestrae into the space of Disse enabling direct hepatocyte interaction, while exhibiting potent ROS scavenging activity and undergoing ROS-triggered morphological degradation that accelerated Tec release under oxidative conditions. In an APAP-induced ALI mouse model, PBHB@Tec markedly attenuated ALI phenotypes. Mechanistically, PBHB@Tec reduced endoplasmic reticulum (ER) stress, which alleviated ER Ca2+ leak and subsequently prevented mitochondrial Ca2+ overload. This, in turn, lowered mitochondrial ROS production and restored antioxidant defenses, collectively disrupting the feedforward calcium/ROS apoptotic cascade. These broad improvements in ER-mitochondrial homeostasis positioning PBHB@Tec as a promising ROS-responsive nanotherapy for APAP-induced hepatotoxicity.
{"title":"ROS-scavenging nanoparticles loaded with tectorigenin protect against acetaminophen-induced hepatotoxicity by interrupting the calcium/ROS-mediated pathogenic endoplasmic reticulum–Mitochondrial signaling cascade","authors":"Yaqi Zhang , Zeyuan Jin , Lvwan Xu , Zilong Zhong , Xinyu Wang , Changyou Gao , Lanjuan Li","doi":"10.1016/j.bioactmat.2025.12.016","DOIUrl":"10.1016/j.bioactmat.2025.12.016","url":null,"abstract":"<div><div>Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI) and acute liver failure (ALF) worldwide, representing a major clinical and public health challenge due to its rapid onset and high morbidity. Current clinical treatment is limited to N-acetylcysteine (NAC), but its efficacy is highly time-dependent and the prolonged regimen imposes additional clinical burdens and side effects. Natural compounds hold tremendous promise for hepatoprotection, but their clinical translation is limited by unfavorable physicochemical and pharmacokinetic properties. In this study, tectorigenin (Tec), an isoflavone possessing anti-inflammatory and antioxidative activity, was encapsulated within a reactive oxygen species (ROS)-responsive nanoplatform (PBHB@Tec) to enhance bioavailability and enable site-selective hepatoprotection. PBHB@Tec possessed diameters compatible with passage through hepatic sinusoidal fenestrae into the space of Disse enabling direct hepatocyte interaction, while exhibiting potent ROS scavenging activity and undergoing ROS-triggered morphological degradation that accelerated Tec release under oxidative conditions. In an APAP-induced ALI mouse model, PBHB@Tec markedly attenuated ALI phenotypes. Mechanistically, PBHB@Tec reduced endoplasmic reticulum (ER) stress, which alleviated ER Ca<sup>2+</sup> leak and subsequently prevented mitochondrial Ca<sup>2+</sup> overload. This, in turn, lowered mitochondrial ROS production and restored antioxidant defenses, collectively disrupting the feedforward calcium/ROS apoptotic cascade. These broad improvements in ER-mitochondrial homeostasis positioning PBHB@Tec as a promising ROS-responsive nanotherapy for APAP-induced hepatotoxicity.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 408-421"},"PeriodicalIF":18.0,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797543","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 : 2025-12-12DOI: 10.1016/j.bioactmat.2025.12.007
Wanli Yu , Zhiyu Chen , Bo Wu , Chunfan Zhang , Ying Han , Dewei Zou , Jianxiang Zhang , Nan Wu
Intracerebral hemorrhage (ICH) is a life-threatening neurological disorder characterized by spatiotemporally evolving pathological cascades, necessitating interventions that dynamically adapt to its multiphasic injury progression. Here, we report modular polymer (PPP)-based nanotherapeutics engineered for stage-specific therapy of ICH through sequential pharmacological actions. The PPP architecture integrates a hydrophilic segment and a hydrophobic, reactive oxygen species (ROS)-responsive motif onto a polyamine scaffold, enabling ROS-triggered programmed dissociation, on-demand anti-inflammatory agent release, and iron chelation. This design confers spatiotemporal therapeutic precision: during the hyperacute phase, PPP nanoparticles promote rapid hemostasis and efficiently scavenge cell-free DNA (cfDNA); in the acute phase, they attenuate neuroinflammation through ROS-mediated hydrolysis and subsequent release of polyamine domains; and in the subacute phase, the exposed polyamines neutralize cytotoxic aldehydes and sequester iron ions to suppress ferroptosis. In vitro, PPPs demonstrated multimodal cytoprotection by attenuating oxidative stress and inflammation in microglial cells under hemin/cfDNA challenge, thereby preserving neuronal viability, and directly inhibiting neuronal ferroptosis via downregulating heme oxygenase-1 and activating glutathione peroxidase 4/solute carrier family 7 member 11. In vivo, PPPs conferred comprehensive neuroprotection, significantly limiting hematoma expansion, reducing oxidative stress and neuroinflammation, and preventing iron-mediated neuronal death. By precisely interfacing with dynamic pathophysiology of ICH, this tunable nanotherapeutic platform represents a paradigm shift in targeted neurovascular injury management.
{"title":"Modular nanotherapeutics with spatiotemporal precision for phase-specific treatment of intracerebral hemorrhage","authors":"Wanli Yu , Zhiyu Chen , Bo Wu , Chunfan Zhang , Ying Han , Dewei Zou , Jianxiang Zhang , Nan Wu","doi":"10.1016/j.bioactmat.2025.12.007","DOIUrl":"10.1016/j.bioactmat.2025.12.007","url":null,"abstract":"<div><div>Intracerebral hemorrhage (ICH) is a life-threatening neurological disorder characterized by spatiotemporally evolving pathological cascades, necessitating interventions that dynamically adapt to its multiphasic injury progression. Here, we report modular polymer (PPP)-based nanotherapeutics engineered for stage-specific therapy of ICH through sequential pharmacological actions. The PPP architecture integrates a hydrophilic segment and a hydrophobic, reactive oxygen species (ROS)-responsive motif onto a polyamine scaffold, enabling ROS-triggered programmed dissociation, on-demand anti-inflammatory agent release, and iron chelation. This design confers spatiotemporal therapeutic precision: during the hyperacute phase, PPP nanoparticles promote rapid hemostasis and efficiently scavenge cell-free DNA (cfDNA); in the acute phase, they attenuate neuroinflammation through ROS-mediated hydrolysis and subsequent release of polyamine domains; and in the subacute phase, the exposed polyamines neutralize cytotoxic aldehydes and sequester iron ions to suppress ferroptosis. In vitro, PPPs demonstrated multimodal cytoprotection by attenuating oxidative stress and inflammation in microglial cells under hemin/cfDNA challenge, thereby preserving neuronal viability, and directly inhibiting neuronal ferroptosis via downregulating heme oxygenase-1 and activating glutathione peroxidase 4/solute carrier family 7 member 11. In vivo, PPPs conferred comprehensive neuroprotection, significantly limiting hematoma expansion, reducing oxidative stress and neuroinflammation, and preventing iron-mediated neuronal death. By precisely interfacing with dynamic pathophysiology of ICH, this tunable nanotherapeutic platform represents a paradigm shift in targeted neurovascular injury management.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 331-347"},"PeriodicalIF":18.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748146","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 : 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":"2025-12-12","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 : 2025-12-12DOI: 10.1016/j.bioactmat.2025.12.004
Yifei Niu , Saiqun Li , Fei Yu , Xuan Zhao , Jin Yuan
Ocular adhesive bioactive materials represent a paradigm shift in ophthalmic surgery and tissue repair, offering sutureless solutions with enhanced biocompatibility, reduced complications, and improved clinical outcomes. Designed to function as sealants, defect fillers, and delivery vehicles for drugs or cells, these materials must meet the stringent physiological and optical demands of the ocular environment. They are typically classified by anatomical application (ocular surface vs. fundus) and material origin (natural vs. synthetic), and rely on diverse crosslinking strategies to achieve tailored mechanical and adhesive properties. Current design approaches increasingly embrace biomimetic principles—aiming to replicate the structural and functional characteristics of native ocular tissues—to improve integration and therapeutic effectiveness. Moreover, the combination of adhesive materials with regenerative therapies such as stem cells, and exosomes extends their potential from simple structural support to active tissue regeneration. This review provides a comprehensive synthesis of ocular adhesive bioactive materials, outlines major design strategies and applications, and highlights future directions toward personalized and programmable regenerative platforms capable of addressing complex ophthalmic challenges.
{"title":"Adhesive bioactive materials in ocular applications: Toward smart, regenerative, and minimally invasive therapies","authors":"Yifei Niu , Saiqun Li , Fei Yu , Xuan Zhao , Jin Yuan","doi":"10.1016/j.bioactmat.2025.12.004","DOIUrl":"10.1016/j.bioactmat.2025.12.004","url":null,"abstract":"<div><div>Ocular adhesive bioactive materials represent a paradigm shift in ophthalmic surgery and tissue repair, offering sutureless solutions with enhanced biocompatibility, reduced complications, and improved clinical outcomes. Designed to function as sealants, defect fillers, and delivery vehicles for drugs or cells, these materials must meet the stringent physiological and optical demands of the ocular environment. They are typically classified by anatomical application (ocular surface vs. fundus) and material origin (natural vs. synthetic), and rely on diverse crosslinking strategies to achieve tailored mechanical and adhesive properties. Current design approaches increasingly embrace biomimetic principles—aiming to replicate the structural and functional characteristics of native ocular tissues—to improve integration and therapeutic effectiveness. Moreover, the combination of adhesive materials with regenerative therapies such as stem cells, and exosomes extends their potential from simple structural support to active tissue regeneration. This review provides a comprehensive synthesis of ocular adhesive bioactive materials, outlines major design strategies and applications, and highlights future directions toward personalized and programmable regenerative platforms capable of addressing complex ophthalmic challenges.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 303-330"},"PeriodicalIF":18.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145748145","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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