Pub Date : 2026-01-09DOI: 10.1016/j.bioactmat.2026.01.007
Yanyang Chen , Wei He , Shifeng Ling , Yang Zhou , Jie Chen , Yawei Du , Ran Mo , Wenguo Cui
mRNA therapy holds immense promise for regenerative medicine; however, localized endoplasmic reticulum stress (ERS) in damaged tissues can impair the critical process of ribosomal translation. Here, we developed an in situ injectable lipid nanoparticle (LNP)/microsphere complex, also referred to as a lipid-hydrogel microplex (iLMP), with ERS-alleviating functionality to increase ribosomal translation. A vitamin E-derived ionizable lipid was synthesized to replace conventional ionizable lipids in LNPs, whereas porous hydrogel microspheres stabilized the LNPs via physical adsorption. In vitro studies revealed that the iLMPs codelivered vitamin E and mRNA, mitigating ERS and reducing eIF2α phosphorylation, a key translational barrier. Additionally, iLMPs injected in situ rapidly reconstructed the extracellular matrix, promoting tissue repair. In a bone defect animal model, iLMPs significantly enhanced BMP-2 mRNA translation, promoting osteogenesis. In summary, we present a novel in situ injectable mRNA delivery platform that enhances ribosomal translation, offering a promising strategy for tissue regeneration.
{"title":"Boosting ribosomal translation via ionizable lipid-hydrogel microplexes for localized mRNA therapy","authors":"Yanyang Chen , Wei He , Shifeng Ling , Yang Zhou , Jie Chen , Yawei Du , Ran Mo , Wenguo Cui","doi":"10.1016/j.bioactmat.2026.01.007","DOIUrl":"10.1016/j.bioactmat.2026.01.007","url":null,"abstract":"<div><div>mRNA therapy holds immense promise for regenerative medicine; however, localized endoplasmic reticulum stress (ERS) in damaged tissues can impair the critical process of ribosomal translation. Here, we developed an <em>in situ</em> injectable lipid nanoparticle (LNP)/microsphere complex, also referred to as a lipid-hydrogel microplex (iLMP), with ERS-alleviating functionality to increase ribosomal translation. A vitamin E-derived ionizable lipid was synthesized to replace conventional ionizable lipids in LNPs, whereas porous hydrogel microspheres stabilized the LNPs <em>via</em> physical adsorption. <em>In vitro</em> studies revealed that the iLMPs codelivered vitamin E and mRNA, mitigating ERS and reducing eIF2α phosphorylation, a key translational barrier. Additionally, iLMPs injected <em>in situ</em> rapidly reconstructed the extracellular matrix, promoting tissue repair. In a bone defect animal model, iLMPs significantly enhanced BMP-2 mRNA translation, promoting osteogenesis. In summary, we present a novel <em>in situ</em> injectable mRNA delivery platform that enhances ribosomal translation, offering a promising strategy for tissue regeneration.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"59 ","pages":"Pages 678-696"},"PeriodicalIF":18.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922349","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 : 2026-01-08DOI: 10.1016/j.bioactmat.2025.12.056
Mo Zhang , Fan Xu , Jingcheng Cao , Shihang Liu , Kehao Li , Ya Zhang , Yawen Chen , Siming Jia , Yuhang Shi , Kai Kang , Xiaofeng Du , Tao Zhang , Jing Wang , Wei Chen
Fracture nonunion or delayed union presents a significant challenge in orthopedic practice. Bone healing is a complex physiological process that initiates with the modulation of inflammatory immunity and progresses through critical stages, including angiogenesis, osteogenic differentiation, and biomineralization. The intrinsic link among immune homeostasis, bacterial clearance, and osteogenic microenvironments underscores the need for an integrated therapeutic strategy. To address these challenges, we developed a multifunctional molybdenum-based polyoxometalate cluster (Mo-POM) modified with gallic acid (GA). Theoretical and experimental evidence confirms that electron transfer from GA to the Mo-POM cluster narrows the HOMO-LUMO energy gap, enhancing its multi-enzyme mimetic activity for effective reactive oxygen species (ROS) scavenging, thereby remodeling the immune microenvironment. The Mo-POM also exhibits broad-spectrum antibacterial function through synergistic disruption of bacterial membranes and biofilms. To ensure practical applicability and sustained release, the Mo-POM was encapsulated within a gellan gum/nano-hydroxyapatite (GG/nHA) hydrogel scaffold. The resulting Mo-POM@GG/nHA system effectively coordinates early immunomodulation and antibacterial activity with enhanced biomineralization in the bone regeneration process. Although polyoxometalates have demonstrated versatile biochemical properties, their application in bone regeneration remains largely unexplored. This work demonstrates that a single Mo-POM cluster acts as a core modulator, achieving the “three birds with one stone” effect by eliminating inflammation, modulating the immune microenvironment, and boosting osteogenesis, thereby providing a new avenue for designing a new class of integrated biomaterials for orthopedic applications.
{"title":"Multifunctional polyoxomolybdate cluster loaded into hydrogel for augmented bone regeneration through synergistic immunomodulation and osteogenesis","authors":"Mo Zhang , Fan Xu , Jingcheng Cao , Shihang Liu , Kehao Li , Ya Zhang , Yawen Chen , Siming Jia , Yuhang Shi , Kai Kang , Xiaofeng Du , Tao Zhang , Jing Wang , Wei Chen","doi":"10.1016/j.bioactmat.2025.12.056","DOIUrl":"10.1016/j.bioactmat.2025.12.056","url":null,"abstract":"<div><div>Fracture nonunion or delayed union presents a significant challenge in orthopedic practice. Bone healing is a complex physiological process that initiates with the modulation of inflammatory immunity and progresses through critical stages, including angiogenesis, osteogenic differentiation, and biomineralization. The intrinsic link among immune homeostasis, bacterial clearance, and osteogenic microenvironments underscores the need for an integrated therapeutic strategy. To address these challenges, we developed a multifunctional molybdenum-based polyoxometalate cluster (Mo-POM) modified with gallic acid (GA). Theoretical and experimental evidence confirms that electron transfer from GA to the Mo-POM cluster narrows the HOMO-LUMO energy gap, enhancing its multi-enzyme mimetic activity for effective reactive oxygen species (ROS) scavenging, thereby remodeling the immune microenvironment. The Mo-POM also exhibits broad-spectrum antibacterial function through synergistic disruption of bacterial membranes and biofilms. To ensure practical applicability and sustained release, the Mo-POM was encapsulated within a gellan gum/nano-hydroxyapatite (GG/nHA) hydrogel scaffold. The resulting Mo-POM@GG/nHA system effectively coordinates early immunomodulation and antibacterial activity with enhanced biomineralization in the bone regeneration process. Although polyoxometalates have demonstrated versatile biochemical properties, their application in bone regeneration remains largely unexplored. This work demonstrates that a single Mo-POM cluster acts as a core modulator, achieving the “three birds with one stone” effect by eliminating inflammation, modulating the immune microenvironment, and boosting osteogenesis, thereby providing a new avenue for designing a new class of integrated biomaterials for orthopedic applications.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"59 ","pages":"Pages 662-677"},"PeriodicalIF":18.0,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922345","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 : 2026-01-07DOI: 10.1016/j.bioactmat.2026.01.004
Zitian Zheng , Yichen Hu , Yucheng Zhu , Hanchen Zhang , Meng Yang , Guocheng Ding , Yang Wu , Fan Yang , Boyun Lu , Zheng Zhou , Xiaojun Liu , Guanxin Zhang , Xin Zhang , Deqing Zhang , Jianquan Wang , Hongjie Huang
Achilles tendinopathy represents a prototypical musculoskeletal disorder driven by a self-perpetuating “inflammaging” vicious cycle, where chronic inflammation and stem cell senescence mutually reinforce to precipitate tissue failure. Current therapeutics inadequately address the complex intercellular signaling fueling this loop. Herein, we present a reactive oxygen species (ROS)-responsive photothermal cascade nanoplatform (LT-NPs) that couples Licochalcone A delivery with mild near-infrared (NIR) hyperthermia (∼42 °C). Unlike conventional ablative therapies, this platform leverages mild thermal stress as a safe, generalized immunometabolic modulator. Mechanistically, we identify the mitochondrial DNA (mtDNA)-cGAS-STING axis as the pivotal “bridge” connecting mitochondrial dysfunction to immune dysregulation. The LT-NPs-NIR system dismantles this pathology via a synergistic “dual-lock” strategy: (1) mild photothermal heating induces heat shock protein 70 (HSP70) to seal mtDNA leakage; and (2) released Licochalcone A directly inhibits the downstream STING sensor. Crucially, this intervention re-engineers the dysregulated crosstalk between the immune niche and tendon stroma: by reprogramming M1 macrophages toward a reparative M2 phenotype and simultaneously rescuing tendon stem/progenitor cells (TSPCs) from senescence-associated secretory phenotype (SASP)-mediated senescence, the platform effectively uncouples the reciprocal feedback loop between inflammation and degeneration. In vivo, this orchestrated restoration of the microenvironment significantly suppresses heterotopic ossification and recovers biomechanical function. Consequently, the “mild photothermal cascade” concept establishes a versatile therapeutic paradigm, offering a scalable strategy to resolve the intricate inflammation-senescence crosstalk across a broad spectrum of age-related pathologies.
{"title":"On-demand mild photothermal cascade platform reprogramming mitochondrial immunity for tendon rejuvenation","authors":"Zitian Zheng , Yichen Hu , Yucheng Zhu , Hanchen Zhang , Meng Yang , Guocheng Ding , Yang Wu , Fan Yang , Boyun Lu , Zheng Zhou , Xiaojun Liu , Guanxin Zhang , Xin Zhang , Deqing Zhang , Jianquan Wang , Hongjie Huang","doi":"10.1016/j.bioactmat.2026.01.004","DOIUrl":"10.1016/j.bioactmat.2026.01.004","url":null,"abstract":"<div><div>Achilles tendinopathy represents a prototypical musculoskeletal disorder driven by a self-perpetuating “inflammaging” vicious cycle, where chronic inflammation and stem cell senescence mutually reinforce to precipitate tissue failure. Current therapeutics inadequately address the complex intercellular signaling fueling this loop. Herein, we present a reactive oxygen species (ROS)-responsive photothermal cascade nanoplatform (LT-NPs) that couples Licochalcone A delivery with mild near-infrared (NIR) hyperthermia (∼42 °C). Unlike conventional ablative therapies, this platform leverages mild thermal stress as a safe, generalized immunometabolic modulator. Mechanistically, we identify the mitochondrial DNA (mtDNA)-cGAS-STING axis as the pivotal “bridge” connecting mitochondrial dysfunction to immune dysregulation. The LT-NPs-NIR system dismantles this pathology via a synergistic “dual-lock” strategy: (1) mild photothermal heating induces heat shock protein 70 (HSP70) to seal mtDNA leakage; and (2) released Licochalcone A directly inhibits the downstream STING sensor. Crucially, this intervention re-engineers the dysregulated crosstalk between the immune niche and tendon stroma: by reprogramming M1 macrophages toward a reparative M2 phenotype and simultaneously rescuing tendon stem/progenitor cells (TSPCs) from senescence-associated secretory phenotype (SASP)-mediated senescence, the platform effectively uncouples the reciprocal feedback loop between inflammation and degeneration. In vivo, this orchestrated restoration of the microenvironment significantly suppresses heterotopic ossification and recovers biomechanical function. Consequently, the “mild photothermal cascade” concept establishes a versatile therapeutic paradigm, offering a scalable strategy to resolve the intricate inflammation-senescence crosstalk across a broad spectrum of age-related pathologies.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"59 ","pages":"Pages 642-661"},"PeriodicalIF":18.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922337","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 : 2026-01-07DOI: 10.1016/j.bioactmat.2025.11.044
Yuanqi Ma , Xingqi Song , Bin Luo , Baoshuai Bai , Chen Jin , Shanhong Xie , Meilin Huang , Jie Luo , Zhengwei You , Dong Lei , Guangdong Zhou
The harsh microenvironment characterized by avascularity and hypoxia presents a significant challenge for bone regeneration following refractory bone defects. Tissue engineering combined with electrotherapy has emerged as a promising alternative for repairing bone defects, offering advantages such as accelerated healing and the restoration of physiological functions in regenerated bone. In this study, we propose a strategy for constructing tissue-engineered cartilage derived from bone marrow stem cells (BMSCs) for bone regeneration, utilizing 3D-printed triboelectric scaffolds (TES). The TES scaffold is fabricated from biodegradable bioelastomer and conductive biomaterial, featuring excellent biomimetic elasticity and hydrophobicity. The TES contains numerous hydrophobic microporous units, enabling in situ self-powered stimulation in vivo. The conductivity of the TES has been shown to enhance the chondrogenic differentiation potential of BMSCs during in vitro induction into tissue-engineered cartilage. Notably, the TES scaffold was more effective in promoting endochondral ossification of tissue-engineered cartilage in vivo. The in vivo osteogenesis mechanism of the TES group was further analyzed through proteomics, revealing that TES facilitated actin cytoskeleton remodeling, activated the PI3K-Akt pathway, provided metabolic support, and enhanced intercellular communication to drive the endochondral ossification process. Finally, in situ skull defect repair in rabbits successfully demonstrated the efficacy of TES electrical stimulation in promoting tissue-engineered endochondral ossification, thereby achieving bone defect regeneration and providing an effective biological strategy for the repair of refractory bone defects.
{"title":"3D-printed triboelectric scaffolds for fabricating BMSC-derived cartilage to repair bone defects and promote endochondral ossification","authors":"Yuanqi Ma , Xingqi Song , Bin Luo , Baoshuai Bai , Chen Jin , Shanhong Xie , Meilin Huang , Jie Luo , Zhengwei You , Dong Lei , Guangdong Zhou","doi":"10.1016/j.bioactmat.2025.11.044","DOIUrl":"10.1016/j.bioactmat.2025.11.044","url":null,"abstract":"<div><div>The harsh microenvironment characterized by avascularity and hypoxia presents a significant challenge for bone regeneration following refractory bone defects. Tissue engineering combined with electrotherapy has emerged as a promising alternative for repairing bone defects, offering advantages such as accelerated healing and the restoration of physiological functions in regenerated bone. In this study, we propose a strategy for constructing tissue-engineered cartilage derived from bone marrow stem cells (BMSCs) for bone regeneration, utilizing 3D-printed triboelectric scaffolds (TES). The TES scaffold is fabricated from biodegradable bioelastomer and conductive biomaterial, featuring excellent biomimetic elasticity and hydrophobicity. The TES contains numerous hydrophobic microporous units, enabling in situ self-powered stimulation in vivo. The conductivity of the TES has been shown to enhance the chondrogenic differentiation potential of BMSCs during in vitro induction into tissue-engineered cartilage. Notably, the TES scaffold was more effective in promoting endochondral ossification of tissue-engineered cartilage in vivo. The in vivo osteogenesis mechanism of the TES group was further analyzed through proteomics, revealing that TES facilitated actin cytoskeleton remodeling, activated the PI3K-Akt pathway, provided metabolic support, and enhanced intercellular communication to drive the endochondral ossification process. Finally, in situ skull defect repair in rabbits successfully demonstrated the efficacy of TES electrical stimulation in promoting tissue-engineered endochondral ossification, thereby achieving bone defect regeneration and providing an effective biological strategy for the repair of refractory bone defects.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 685-700"},"PeriodicalIF":18.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939000","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 : 2026-01-06DOI: 10.1016/j.bioactmat.2025.12.006
Jialing Cheng , Guo Bao , Demin Lin , Hongliang Wang , Yanfang Yang , Youbai Chen , Meiying Ning , Jun Ye , Yuling Liu
Skin aging is characterized by a progressive decline in regenerative capacity, primarily driven by fibroblast senescence, oxidative stress, chronic inflammation, and the degradation of type I/III collagen, culminating in an extracellular matrix (ECM) imbalance. Current injectable fillers—such as hyaluronic acid, collagen, and PLLA—provide temporary structural support but fail to address the underlying cellular senescence or restore ECM homeostasis, highlighting the need for regenerative biomaterials. Silk fibroin (SF), a natural protein, self-assembles into a β-sheet-rich scaffold that structurally supports fibroblasts in depositing collagen and elastin, thereby improving the skin's ECM, accelerating wound healing, and promoting tissue regeneration. However, its role in modulating fibroblast senescence and ECM remodeling remains unclear. This study demonstrates that SF provides a suitable microenvironment for the adhesion and proliferation of fibroblasts, reducing the accumulation of SASP factors and facilitating the transition of fibroblasts from a senescent to a functional state. Furthermore, SF improves the skin microenvironment by reducing reactive oxygen species (ROS) and matrix metalloproteinase (MMP) expression through modulation of the ROS–MAPK–AP-1–MMP signal pathway, thereby delaying collagen degradation in aged skin. These findings reveal that SF uniquely rejuvenates fibroblasts and restores ECM homeostasis through a non-inflammatory mechanism, distinguishing it from conventional fillers that rely on inflammatory pathways for collagen induction. This work establishes SF as a next-generation injectable biomaterial with dual targeting of cellular senescence and ECM imbalance, offering a transformative strategy for regenerative dermatology and personalized anti-aging approaches.
皮肤老化的特征是再生能力的逐渐下降，主要是由成纤维细胞衰老、氧化应激、慢性炎症和I/III型胶原蛋白的降解所驱动，最终导致细胞外基质（ECM）失衡。目前的可注射填充剂，如透明质酸、胶原蛋白和pla，提供暂时的结构支持，但不能解决潜在的细胞衰老或恢复ECM稳态，突出了对再生生物材料的需求。丝素蛋白（SF）是一种天然蛋白质，可以自我组装成富含β的支架，在结构上支持成纤维细胞沉积胶原蛋白和弹性蛋白，从而改善皮肤的ECM，加速伤口愈合，促进组织再生。然而，其在调节成纤维细胞衰老和ECM重塑中的作用尚不清楚。本研究表明，SF为成纤维细胞的粘附和增殖提供了适宜的微环境，减少了SASP因子的积累，促进了成纤维细胞从衰老状态向功能状态的转变。此外，SF通过调节ROS - mapk - ap -1 - MMP信号通路，减少活性氧（ROS）和基质金属蛋白酶（MMP）的表达，从而延缓老化皮肤中胶原蛋白的降解，从而改善皮肤微环境。这些发现表明，SF独特地通过非炎症机制使成纤维细胞恢复活力并恢复ECM稳态，这与依赖炎症途径诱导胶原的传统填充物不同。本研究确立了SF作为下一代可注射生物材料的双重靶向细胞衰老和ECM失衡，为再生皮肤病学和个性化抗衰老方法提供了一种变革策略。
{"title":"Silk Fibroin Counteracts Fibroblast Senescence to Restore ECM Homeostasis in Aged Skin","authors":"Jialing Cheng , Guo Bao , Demin Lin , Hongliang Wang , Yanfang Yang , Youbai Chen , Meiying Ning , Jun Ye , Yuling Liu","doi":"10.1016/j.bioactmat.2025.12.006","DOIUrl":"10.1016/j.bioactmat.2025.12.006","url":null,"abstract":"<div><div>Skin aging is characterized by a progressive decline in regenerative capacity, primarily driven by fibroblast senescence, oxidative stress, chronic inflammation, and the degradation of type I/III collagen, culminating in an extracellular matrix (ECM) imbalance. Current injectable fillers—such as hyaluronic acid, collagen, and PLLA—provide temporary structural support but fail to address the underlying cellular senescence or restore ECM homeostasis, highlighting the need for regenerative biomaterials. Silk fibroin (SF), a natural protein, self-assembles into a β-sheet-rich scaffold that structurally supports fibroblasts in depositing collagen and elastin, thereby improving the skin's ECM, accelerating wound healing, and promoting tissue regeneration. However, its role in modulating fibroblast senescence and ECM remodeling remains unclear. This study demonstrates that SF provides a suitable microenvironment for the adhesion and proliferation of fibroblasts, reducing the accumulation of SASP factors and facilitating the transition of fibroblasts from a senescent to a functional state. Furthermore, SF improves the skin microenvironment by reducing reactive oxygen species (ROS) and matrix metalloproteinase (MMP) expression through modulation of the ROS–MAPK–AP-1–MMP signal pathway, thereby delaying collagen degradation in aged skin. These findings reveal that SF uniquely rejuvenates fibroblasts and restores ECM homeostasis through a non-inflammatory mechanism, distinguishing it from conventional fillers that rely on inflammatory pathways for collagen induction. This work establishes SF as a next-generation injectable biomaterial with dual targeting of cellular senescence and ECM imbalance, offering a transformative strategy for regenerative dermatology and personalized anti-aging approaches.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"58 ","pages":"Pages 666-684"},"PeriodicalIF":18.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939002","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 : 2026-01-06DOI: 10.1016/j.bioactmat.2026.01.002
Wen-Jie Zhang , Bei-Min Tian , Fang Li , Xuan Li , Rui-Xin Wu , Yuan Yin , Jia Wang , Dao-Kun Deng , Yu-Zhe Chen , Hong-Yu Wang , Yu-Xuan Du , Xuan Wang , Yin Xiao , Xiao-Tao He , Fa-Ming Chen
Modulating macrophage phenotype and function via immunometabolic reprogramming represents a new therapeutic paradigm to combat chronic inflammatory diseases such as periodontitis. Tetrameric pyruvate kinase M2 (Tet-PKM2), a highly active metabolic enzyme involved in the flux of glucose-derived carbons into the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), was found to be dramatically decreased in response to inflammation, rendering a potential immunometabolic target for developping new therapeutics. Hence, we report a large extracellular vesicle (LEV) that is bioengineered to intracellularly deliver Tet-PKM2 for the reprogramming of proinflammatory macrophages and the restoration of their aberrant immunometabolism. We engineered Tet-PKM2-enriched LEVs modified by tannic acid (LEVsTet−PKM2@TA) that can intracellularly deliver Tet-PKM2 and increase their ability to escape lysosomal degradation for the intracellular delivery of Tet-PKM2. In vitro, LEVsTet−PKM2@TA were able to rescue aberrant pyruvate metabolism in lipopolysaccharide (LPS)-activated macrophages by increasing TCA cycle activity and enhancing mitochondrial OXPHOS metabolism. In vivo, LEVsTet−PKM2@TA exerted robust immunomodulatory effects by increasing pyruvate kinase (PK) activity and coaxing macrophages toward the M2 phenotype, ultimately resulting in robust periodontal tissue regeneration in a mouse ligature-induced periodontitis model. This study provides a versatile and safe method for the targeted delivery of Tet-PKM2 via EVs to modulate macrophage phenotype and function. Our work demonstrates a new concept for immunometabolic reprogramming to treat chronic inflammatory diseases.
{"title":"Bioengineered extracellular vesicles escape lysosomal degradation and deliver Tet-PKM2 for macrophage immunometabolic reprogramming and periodontitis treatment","authors":"Wen-Jie Zhang , Bei-Min Tian , Fang Li , Xuan Li , Rui-Xin Wu , Yuan Yin , Jia Wang , Dao-Kun Deng , Yu-Zhe Chen , Hong-Yu Wang , Yu-Xuan Du , Xuan Wang , Yin Xiao , Xiao-Tao He , Fa-Ming Chen","doi":"10.1016/j.bioactmat.2026.01.002","DOIUrl":"10.1016/j.bioactmat.2026.01.002","url":null,"abstract":"<div><div>Modulating macrophage phenotype and function via immunometabolic reprogramming represents a new therapeutic paradigm to combat chronic inflammatory diseases such as periodontitis. Tetrameric pyruvate kinase M2 (Tet-PKM2), a highly active metabolic enzyme involved in the flux of glucose-derived carbons into the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), was found to be dramatically decreased in response to inflammation, rendering a potential immunometabolic target for developping new therapeutics. Hence, we report a large extracellular vesicle (LEV) that is bioengineered to intracellularly deliver Tet-PKM2 for the reprogramming of proinflammatory macrophages and the restoration of their aberrant immunometabolism. We engineered Tet-PKM2-enriched LEVs modified by tannic acid (LEVs<sup>Tet−PKM2</sup>@TA) that can intracellularly deliver Tet-PKM2 and increase their ability to escape lysosomal degradation for the intracellular delivery of Tet-PKM2. <em>In vitro</em>, LEVs<sup>Tet−PKM2</sup>@TA were able to rescue aberrant pyruvate metabolism in lipopolysaccharide (LPS)-activated macrophages by increasing TCA cycle activity and enhancing mitochondrial OXPHOS metabolism. <em>In vivo</em>, LEVs<sup>Tet−PKM2</sup>@TA exerted robust immunomodulatory effects by increasing pyruvate kinase (PK) activity and coaxing macrophages toward the M2 phenotype, ultimately resulting in robust periodontal tissue regeneration in a mouse ligature-induced periodontitis model. This study provides a versatile and safe method for the targeted delivery of Tet-PKM2 via EVs to modulate macrophage phenotype and function. Our work demonstrates a new concept for immunometabolic reprogramming to treat chronic inflammatory diseases.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"59 ","pages":"Pages 607-628"},"PeriodicalIF":18.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922348","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 : 2026-01-06DOI: 10.1016/j.bioactmat.2025.12.040
Hung Pang Lee , Michelle Tai , Sarah J. Jones , Xinming Tong , Sungwon Kim , Michelle M.T. Jansman , Tony Tam , Jianyi Du , Mark A. Skylar-Scott , Fan Yang
Granular microgels are attractive bioinks for bioprinting due to their injectability, printability, modularity, and enhanced macroporosity compared to conventional nanoporous hydrogels. Despite the potential of microgels for bioprinting, most previous work has relied on spherical microgels and produced isotropic tissues, whereas many native tissues are inherently anisotropic. While emerging studies have explored non-spherical microgels for bioprinting, there remains a need for bioinks that support cell alignment and tunable niche cues. Microribbons (μRB) are anisotropic ribbon-shaped microgels, but the potential of μRBs as bioinks for printing 3D anisotropic tissues remains unexplored. Here, we report the development of μRBs with tunable stiffness as bioinks for extrusion-based bioprinting and demonstrate that μRB bioinks maintain excellent printability and align during extrusion. μRB bioinks support alignment of MSCs and endothelial cells, with greater alignment as μRB stiffness increases. Increasing μRB stiffness also accelerates mesenchymal stromal cell osteogenesis in 3D. Finally, we demonstrate the potential of μRB bioinks for modeling breast cancer-bone metastasis, which features spatial patterning of multiple cell types to model cancer cell invasion at the tissue interface. Together, these results establish ribbon-shaped microgels as a new class of anisotropic bioinks, offering a versatile platform to support a broad range of bioprinting applications.
{"title":"Ribbon-shaped microgels as bioinks for 3D bioprinting of anisotropic tissue structures","authors":"Hung Pang Lee , Michelle Tai , Sarah J. Jones , Xinming Tong , Sungwon Kim , Michelle M.T. Jansman , Tony Tam , Jianyi Du , Mark A. Skylar-Scott , Fan Yang","doi":"10.1016/j.bioactmat.2025.12.040","DOIUrl":"10.1016/j.bioactmat.2025.12.040","url":null,"abstract":"<div><div>Granular microgels are attractive bioinks for bioprinting due to their injectability, printability, modularity, and enhanced macroporosity compared to conventional nanoporous hydrogels. Despite the potential of microgels for bioprinting, most previous work has relied on spherical microgels and produced isotropic tissues, whereas many native tissues are inherently anisotropic. While emerging studies have explored non-spherical microgels for bioprinting, there remains a need for bioinks that support cell alignment and tunable niche cues. Microribbons (μRB) are anisotropic ribbon-shaped microgels, but the potential of μRBs as bioinks for printing 3D anisotropic tissues remains unexplored. Here, we report the development of μRBs with tunable stiffness as bioinks for extrusion-based bioprinting and demonstrate that μRB bioinks maintain excellent printability and align during extrusion. μRB bioinks support alignment of MSCs and endothelial cells, with greater alignment as μRB stiffness increases. Increasing μRB stiffness also accelerates mesenchymal stromal cell osteogenesis in 3D. Finally, we demonstrate the potential of μRB bioinks for modeling breast cancer-bone metastasis, which features spatial patterning of multiple cell types to model cancer cell invasion at the tissue interface. Together, these results establish ribbon-shaped microgels as a new class of anisotropic bioinks, offering a versatile platform to support a broad range of bioprinting applications.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"59 ","pages":"Pages 595-606"},"PeriodicalIF":18.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922347","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 : 2026-01-06DOI: 10.1016/j.bioactmat.2025.12.055
Xiaojing Zhang , Kexin Li , Yingqi Liu , Yi Han , Kun Xu , Xi Rao , Selvakumar Murugesan , Valentim A.R. Barão , En-Tang Kang , Liqun Xu
Bacterial infection, peri-implant inflammation, and poor osseointegration are primary causes of failure in titanium (Ti)-based implants. Surface functionalization provides a simple and effective strategy to overcome these challenges. In this study, we developed a multifunctional coating based on porous graphdiyne (GDY) nanofilm loaded with shikonin (Skn). GDY was synthesized on Ti surfaces via a copper-catalyzed reaction to form a porous nanostructure. Following Skn loading, a composite layer of tannic acid (TA) and poly (N-isopropylacrylamide) (pNIPAM) was applied, resulting in the Ti-GDY@Skn-TP system. Upon near-infrared (NIR) irradiation, the GDY coating induced localized photothermal effects sufficient to eradicate bacteria. Concurrently, the thermo-responsive release of Skn suppressed early inflammation and promoted osseointegration by regulating macrophage polarization and inflammatory cytokine secretion. In vivo studies confirmed that Ti-GDY@Skn-TP implants effectively eliminated bacterial infections, attenuated acute inflammation, and enhanced bone tissue regeneration and implant integration. This multifunctional approach offers a promising strategy for the surface modification of Ti-based biomedical implants.
{"title":"Shikonin-loaded porous graphdiyne nanofilm on titanium surface for enhanced antibacterial activity and osseointegration","authors":"Xiaojing Zhang , Kexin Li , Yingqi Liu , Yi Han , Kun Xu , Xi Rao , Selvakumar Murugesan , Valentim A.R. Barão , En-Tang Kang , Liqun Xu","doi":"10.1016/j.bioactmat.2025.12.055","DOIUrl":"10.1016/j.bioactmat.2025.12.055","url":null,"abstract":"<div><div>Bacterial infection, peri-implant inflammation, and poor osseointegration are primary causes of failure in titanium (Ti)-based implants. Surface functionalization provides a simple and effective strategy to overcome these challenges. In this study, we developed a multifunctional coating based on porous graphdiyne (GDY) nanofilm loaded with shikonin (Skn). GDY was synthesized on Ti surfaces <em>via</em> a copper-catalyzed reaction to form a porous nanostructure. Following Skn loading, a composite layer of tannic acid (TA) and poly (<em>N</em>-isopropylacrylamide) (pNIPAM) was applied, resulting in the Ti-GDY@Skn-TP system. Upon near-infrared (NIR) irradiation, the GDY coating induced localized photothermal effects sufficient to eradicate bacteria. Concurrently, the thermo-responsive release of Skn suppressed early inflammation and promoted osseointegration by regulating macrophage polarization and inflammatory cytokine secretion. <em>In vivo</em> studies confirmed that Ti-GDY@Skn-TP implants effectively eliminated bacterial infections, attenuated acute inflammation, and enhanced bone tissue regeneration and implant integration. This multifunctional approach offers a promising strategy for the surface modification of Ti-based biomedical implants.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"59 ","pages":"Pages 629-641"},"PeriodicalIF":18.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922346","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 : 2026-01-05DOI: 10.1016/j.bioactmat.2025.12.036
Kaijing Liu , Gen Li , Xiaoyu Liang, Changduo Wang, Ni Zhu, Xue Fu, Yujie Zhang, Chao Liu, Jing Yang
Atherosclerosis (AS) progression is driven by multiple interconnected pathological mechanisms. Among them, vascular senescence is both a key accelerator and consequence, interacting with other processes to promote AS development. Traditional monotherapies were limited to achieve synergistic therapeutic effects due to low oral bioavailability and insufficient multi-target efficacy. To overcome these limitations, we developed a baicalein-copper network (Cu-MON) for oral delivery of atorvastatin (ATV), forming a synergistic therapeutic system (CMA). Cu-MON significantly prolonged the gastrointestinal residence and increased the oral bioavailability of ATV without requiring additional excipients. Crucially, Cu-MON regulated senescence-associated genes, enhanced DNA repair pathways, and mitigated DNA damage, effectively counteracting vascular aging. The integrated CMA system combined enzymatic and non-enzymatic dual antioxidant systems to scavenge multiple ROS species. Furthermore, CMA reprogrammed macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, modulated the PPAR-γ/LXR-α/ABCA-1 pathway to enhance cholesterol efflux, inhibited foam cell formation, and regulated hepatic and systemic cholesterol homeostasis. In ApoE−/− mice, CMA markedly reduced aortic plaque burden and fibrosis, while Cu-MON attenuated key features of AS, including decreased ROS, inflammation, DNA damage, and cellular senescence. The CMA demonstrates high synergistic efficacy and biosafety, offering a novel multi-target oral drug strategy for AS treatment.
{"title":"Carrier free oral Co-delivery of atorvastatin via baicalein-copper-network for atherosclerosis therapy through senescence reversal and multi-mechanistic synergy","authors":"Kaijing Liu , Gen Li , Xiaoyu Liang, Changduo Wang, Ni Zhu, Xue Fu, Yujie Zhang, Chao Liu, Jing Yang","doi":"10.1016/j.bioactmat.2025.12.036","DOIUrl":"10.1016/j.bioactmat.2025.12.036","url":null,"abstract":"<div><div>Atherosclerosis (AS) progression is driven by multiple interconnected pathological mechanisms. Among them, vascular senescence is both a key accelerator and consequence, interacting with other processes to promote AS development. Traditional monotherapies were limited to achieve synergistic therapeutic effects due to low oral bioavailability and insufficient multi-target efficacy. To overcome these limitations, we developed a baicalein-copper network (Cu-MON) for oral delivery of atorvastatin (ATV), forming a synergistic therapeutic system (CMA). Cu-MON significantly prolonged the gastrointestinal residence and increased the oral bioavailability of ATV without requiring additional excipients. Crucially, Cu-MON regulated senescence-associated genes, enhanced DNA repair pathways, and mitigated DNA damage, effectively counteracting vascular aging. The integrated CMA system combined enzymatic and non-enzymatic dual antioxidant systems to scavenge multiple ROS species. Furthermore, CMA reprogrammed macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, modulated the PPAR-γ/LXR-α/ABCA-1 pathway to enhance cholesterol efflux, inhibited foam cell formation, and regulated hepatic and systemic cholesterol homeostasis. In ApoE<sup>−/−</sup> mice, CMA markedly reduced aortic plaque burden and fibrosis, while Cu-MON attenuated key features of AS, including decreased ROS, inflammation, DNA damage, and cellular senescence. The CMA demonstrates high synergistic efficacy and biosafety, offering a novel multi-target oral drug strategy for AS treatment.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"59 ","pages":"Pages 555-578"},"PeriodicalIF":18.0,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922243","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 : 2026-01-05DOI: 10.1016/j.bioactmat.2025.12.052
Xiangwan Miao , Keyu Kong , Kewei Rong , Qianqian Song , Tingxian Guo , Chenyu Zhang , Qiang Wu , Zanjing Zhai , Ye Sun , Yaokai Gan , Mingliang Xiang , Kerong Dai , Anthony Atala , Zuyan Lu
Articular cartilage damage, an important cause of osteoarthritis (OA), is often caused by a senescent cartilage microenvironment and insufficient repair of chondrocytes. These effects are due to limited availability and a depleted stemness phenotype of chondrocyte stem cells, leading to the failure of cartilage repair and exacerbation of symptoms. In this study, a biomimetic gradient-structured cartilage organoid (BGSC-organoid) culture system was developed using decellularized cartilage extracellular matrix infused with extracellular vesicles from SOX9-overexpressing bone marrow-derived stem cells (SBEVs) to induce the rejuvenation of senescent chondrocytes. Single-cell sequencing revealed that a subpopulation of chondrocytes could be rejuvenated in the BGSC-organoid culture system. Moreover, an ex vivo osteoarthritis-on-a-chip (OAOC) model with cyclic mechanical stimulation was constructed to simulate the mechanical microenvironment of cartilage. BGSC-organoids exhibited sustained release of chondrocyte-protective factors and good mechanical resistance through the Vimentin/14-3-3/FOXO3 pathway. Animal studies showed that BGSC-organoids preserved a hyaline-like cartilage phenotype in vivo and delayed the degeneration of articular cartilage and intervertebral discs. Efficient expansion of human cartilage organoids with enhanced regenerative capabilities represents a promising approach for joint regeneration.
{"title":"Construction of biomimetic gradient-structured cartilage organoids and mechanistic study of their application for cartilage rejuvenation","authors":"Xiangwan Miao , Keyu Kong , Kewei Rong , Qianqian Song , Tingxian Guo , Chenyu Zhang , Qiang Wu , Zanjing Zhai , Ye Sun , Yaokai Gan , Mingliang Xiang , Kerong Dai , Anthony Atala , Zuyan Lu","doi":"10.1016/j.bioactmat.2025.12.052","DOIUrl":"10.1016/j.bioactmat.2025.12.052","url":null,"abstract":"<div><div>Articular cartilage damage, an important cause of osteoarthritis (OA), is often caused by a senescent cartilage microenvironment and insufficient repair of chondrocytes. These effects are due to limited availability and a depleted stemness phenotype of chondrocyte stem cells, leading to the failure of cartilage repair and exacerbation of symptoms. In this study, a biomimetic gradient-structured cartilage organoid (BGSC-organoid) culture system was developed using decellularized cartilage extracellular matrix infused with extracellular vesicles from SOX9-overexpressing bone marrow-derived stem cells (SBEVs) to induce the rejuvenation of senescent chondrocytes. Single-cell sequencing revealed that a subpopulation of chondrocytes could be rejuvenated in the BGSC-organoid culture system. Moreover, an ex vivo osteoarthritis-on-a-chip (OAOC) model with cyclic mechanical stimulation was constructed to simulate the mechanical microenvironment of cartilage. BGSC-organoids exhibited sustained release of chondrocyte-protective factors and good mechanical resistance through the Vimentin/14-3-3/FOXO3 pathway. Animal studies showed that BGSC-organoids preserved a hyaline-like cartilage phenotype <em>in vivo</em> and delayed the degeneration of articular cartilage and intervertebral discs. Efficient expansion of human cartilage organoids with enhanced regenerative capabilities represents a promising approach for joint regeneration.</div></div>","PeriodicalId":8762,"journal":{"name":"Bioactive Materials","volume":"59 ","pages":"Pages 579-594"},"PeriodicalIF":18.0,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922247","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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