Pub Date : 2026-02-01Epub Date: 2025-08-06DOI: 10.1016/j.biomaterials.2025.123604
Xuan Li, Xinxin Luo, Ye He, Bikun Zhou, Kun Xu, Qian Huang, Xiao Jiang, Hongwei Xiong, Xuezhe Liu, Shaopeng Liu, Bailong Tao, Peng Liu, Kaiyong Cai
The senescence of mesenchymal stem cells (MSCs) leads to the significant change of their metabolic activity and physiological behaviors. In the context of orthopedic treatment, the osteointegration of titanium implant is largely affected by MSC aging, imposing considerable limitations on its long-term application. In this study, a surface modification on titanium implants was designed to enhance osteointegration by effectively regulating the functions of senescent MSC: A typical micro-nano topological structure was established on the implant surface to improve the osteogenic differentiation of MSCs. Then a functional hydrogel coating was covalently modified to the implant surface through a poly-dopamine layer. For senescent MSCs, firstly, the coating can eliminate the activation of senescence-associated secretory phenotype (SASP) of senescent MSCs by micro-nano topological structure, and it accelerated the proliferation of non-senescent MSCs by the reactive oxygen species (ROS) scavenging. With the degradation of the hydrogel coating, the composition of stem cell pool around the implant interfaces gradually rejuvenated, as the number of non-senescent MSCs increased and senescent MSCs decreased. Meanwhile, the exposed micro-nano topological structure showed significant effect on the osteogenic differentiation of MSCs, and ultimately promoted the osteointegration in aging rats. These results provided promising insights for the design and application of orthopedic titanium implants for aging patients.
{"title":"Enhanced osteointegration of implants in aged rats via a stem cell pool aging reversion strategy.","authors":"Xuan Li, Xinxin Luo, Ye He, Bikun Zhou, Kun Xu, Qian Huang, Xiao Jiang, Hongwei Xiong, Xuezhe Liu, Shaopeng Liu, Bailong Tao, Peng Liu, Kaiyong Cai","doi":"10.1016/j.biomaterials.2025.123604","DOIUrl":"10.1016/j.biomaterials.2025.123604","url":null,"abstract":"<p><p>The senescence of mesenchymal stem cells (MSCs) leads to the significant change of their metabolic activity and physiological behaviors. In the context of orthopedic treatment, the osteointegration of titanium implant is largely affected by MSC aging, imposing considerable limitations on its long-term application. In this study, a surface modification on titanium implants was designed to enhance osteointegration by effectively regulating the functions of senescent MSC: A typical micro-nano topological structure was established on the implant surface to improve the osteogenic differentiation of MSCs. Then a functional hydrogel coating was covalently modified to the implant surface through a poly-dopamine layer. For senescent MSCs, firstly, the coating can eliminate the activation of senescence-associated secretory phenotype (SASP) of senescent MSCs by micro-nano topological structure, and it accelerated the proliferation of non-senescent MSCs by the reactive oxygen species (ROS) scavenging. With the degradation of the hydrogel coating, the composition of stem cell pool around the implant interfaces gradually rejuvenated, as the number of non-senescent MSCs increased and senescent MSCs decreased. Meanwhile, the exposed micro-nano topological structure showed significant effect on the osteogenic differentiation of MSCs, and ultimately promoted the osteointegration in aging rats. These results provided promising insights for the design and application of orthopedic titanium implants for aging patients.</p>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"325 ","pages":"123604"},"PeriodicalIF":12.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803048","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 : 2026-02-01Epub Date: 2025-08-05DOI: 10.1016/j.biomaterials.2025.123602
Ming Li, Shengzhe Zhou, Qiang Yu, Chenxi Wang, Haoyi Chen, Yingying Ma, Huizhen Fan, Tao Ni, Min Lu, Min Yao
Chronic diabetic wounds are characterized by hypoxia, persistent microbial infection, and impaired healing, posing significant challenges to conventional therapies. Herein, we present a novel sprayable double-network hydrogel platform designed to achieve efficient antimicrobial activity and accelerated wound repair under hypoxic conditions by leveraging a type I photodynamic therapy (PDT) and immune-metabolic regulatory strategy. Specifically, we employ salvianolic acid B (SAB) to form a self-assembled hydrogel (SAB-gel) and incorporate fibrin to construct a robust and acidic double-network SAB/F-gel with enhanced mechanical strength and acidic environment. Concurrently, thymoquinone (TQ) and chlorin e6 (Ce6) are self-assembled via hydrophobic interactions to form TQ/Ce6 nanoparticles (TQ/Ce6 NPs) and embedded in the SAB/F-gel, to fabricate the TQ/Ce6@SAB/F-gel. Under low-oxygen conditions, TQ acts as an electron-transfer mediator, enabling Ce6 to generate abundant superoxide anions (·O2-) via type I PDT under red light (RL) irradiation. These ·O2- are subsequently converted into hydrogen peroxide (H2O2) and hydroxyl radicals (·OH) in the acidic environment provided by acidic SAB/F-gel, thereby reducing the dependence on oxygen and maintaining potent antimicrobial efficacy against MRSA, Pseudomonas aeruginosa (Pa), Acinetobacter baumannii (Ab), Escherichia coli (E. coli) and Candida albicans (Ca). In vitro experiments demonstrated that TQ/Ce6@SAB/F-gel regulates macrophage M2 polarization and promotes endothelial cell proliferation, migration, and tube formation via the immune-metabolic regulatory pathways. When applied to MRSA-infected diabetic wounds in mice, the hydrogel in combination with RL completely eradicated bacteria, promoted collagen deposition and angiogenesis, and significantly accelerated wound closure, as demonstrated by histological examination and transcriptome sequencing. This work offers a versatile, biocompatible, and oxygen-independent PDT-based hydrogel system for the treatment of refractory infected diabetic wounds, offering potential for clinical translation and improved patient outcomes.
慢性糖尿病伤口以缺氧、持续微生物感染和愈合受损为特征，对传统治疗提出了重大挑战。在此，我们提出了一种新型的可喷雾双网络水凝胶平台，旨在利用I型光动力疗法（PDT）和免疫代谢调节策略，在缺氧条件下实现有效的抗菌活性和加速伤口修复。具体而言，我们利用丹酚酸B （SAB）形成自组装水凝胶（SAB-gel），并加入纤维蛋白构建坚固的酸性双网络SAB/ f-凝胶，增强了机械强度和酸性环境。同时，百里醌（TQ）和氯e6 （Ce6）通过疏水相互作用自组装形成TQ/Ce6纳米颗粒（TQ/Ce6 NPs）并嵌入SAB/ f-凝胶中，制备TQ/Ce6@SAB/ f-凝胶。在低氧条件下，TQ作为电子转移介质，使Ce6在红光（RL）照射下通过I型PDT产生丰富的超氧阴离子（·O2-）。这些·O2-随后在酸性SAB/ f -凝胶提供的酸性环境中转化为过氧化氢（H2O2）和羟基自由基（·OH），从而降低对氧的依赖，并保持对MRSA、铜绿假单胞菌（Pa）、鲍曼不动杆菌（Ab）、大肠杆菌（E. coli）和白色念珠菌（Ca）的有效抗菌效果。体外实验表明，TQ/Ce6@SAB/F-gel通过免疫代谢调控途径调控巨噬细胞M2极化，促进内皮细胞增殖、迁移和成管。组织学检查和转录组测序结果显示，水凝胶与RL联合应用于mrsa感染的小鼠糖尿病创面，可彻底根除细菌，促进胶原沉积和血管生成，显著加速创面愈合。这项工作为治疗难治性糖尿病感染伤口提供了一种通用的、生物相容性的、不依赖氧的基于pdp的水凝胶系统，为临床转化和改善患者预后提供了潜力。
{"title":"A sprayable TQ/Ce6@SAB/F-gel for accelerating wound healing via hypoxia-tolerant photodynamic therapy and immune-metabolic pathway.","authors":"Ming Li, Shengzhe Zhou, Qiang Yu, Chenxi Wang, Haoyi Chen, Yingying Ma, Huizhen Fan, Tao Ni, Min Lu, Min Yao","doi":"10.1016/j.biomaterials.2025.123602","DOIUrl":"10.1016/j.biomaterials.2025.123602","url":null,"abstract":"<p><p>Chronic diabetic wounds are characterized by hypoxia, persistent microbial infection, and impaired healing, posing significant challenges to conventional therapies. Herein, we present a novel sprayable double-network hydrogel platform designed to achieve efficient antimicrobial activity and accelerated wound repair under hypoxic conditions by leveraging a type I photodynamic therapy (PDT) and immune-metabolic regulatory strategy. Specifically, we employ salvianolic acid B (SAB) to form a self-assembled hydrogel (SAB-gel) and incorporate fibrin to construct a robust and acidic double-network SAB/F-gel with enhanced mechanical strength and acidic environment. Concurrently, thymoquinone (TQ) and chlorin e6 (Ce6) are self-assembled via hydrophobic interactions to form TQ/Ce6 nanoparticles (TQ/Ce6 NPs) and embedded in the SAB/F-gel, to fabricate the TQ/Ce6@SAB/F-gel. Under low-oxygen conditions, TQ acts as an electron-transfer mediator, enabling Ce6 to generate abundant superoxide anions (·O<sub>2</sub><sup>-</sup>) via type I PDT under red light (RL) irradiation. These ·O<sub>2</sub><sup>-</sup> are subsequently converted into hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) and hydroxyl radicals (·OH) in the acidic environment provided by acidic SAB/F-gel, thereby reducing the dependence on oxygen and maintaining potent antimicrobial efficacy against MRSA, Pseudomonas aeruginosa (Pa), Acinetobacter baumannii (Ab), Escherichia coli (E. coli) and Candida albicans (Ca). In vitro experiments demonstrated that TQ/Ce6@SAB/F-gel regulates macrophage M2 polarization and promotes endothelial cell proliferation, migration, and tube formation via the immune-metabolic regulatory pathways. When applied to MRSA-infected diabetic wounds in mice, the hydrogel in combination with RL completely eradicated bacteria, promoted collagen deposition and angiogenesis, and significantly accelerated wound closure, as demonstrated by histological examination and transcriptome sequencing. This work offers a versatile, biocompatible, and oxygen-independent PDT-based hydrogel system for the treatment of refractory infected diabetic wounds, offering potential for clinical translation and improved patient outcomes.</p>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"325 ","pages":"123602"},"PeriodicalIF":12.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811478","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 : 2026-02-01Epub Date: 2025-08-05DOI: 10.1016/j.biomaterials.2025.123595
Yixin Liu, Xinjian Yang, Ya Miao, Taoping Chen, Wenyan Gao, Guoqiang Zhou, Guang Jia, Xiaosong Yang, Jinchao Zhang, Yi Jin
Osteoarthritis (OA), a prevalent degenerative joint disease, currently lacks effective therapeutic options beyond symptomatic relief. Persistent inflammation and impaired cartilage repair accelerate the disease progression. The enzyme inducible nitric oxide synthase (iNOS) contributes to OA by producing nitric oxide (NO), which intensifies inflammation and inhibits cartilage regeneration. Traditional iNOS inhibitors have demonstrated limited efficacy due to inadequate targeted release and uncoordinated control over inflammation. In this study, we developed a self-supported DNAzyme-based DNA hydrogel using rolling circle amplification (RCA) technology to deliver iNOS-targeting DNAzymes and bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) in response to inflammation. The hydrogel incorporates triglycerol monostearate nanoparticles (TGMS NPs), which degrade under high matrix metalloproteinase (MMP) levels in OA joints, thereby triggering the release of the DNAzymes and exosomes with precision. This targeted delivery modulates the inflammatory microenvironment by reducing pro-inflammatory NO production and supports chondrogenesis by promoting M2 macrophage polarization. In vitro and in vivo analyses reveal that the hydrogel significantly reduces inflammatory cytokine levels, enhances chondrocyte proliferation, and restores extracellular matrix integrity, ultimately slowing OA progression. This smart hydrogel offers a promising ambidextrous strategy for microenvironment modulation and cartilage regeneration, potentially advancing OA treatment.
骨关节炎（OA）是一种常见的退行性关节疾病，目前除了症状缓解之外缺乏有效的治疗选择。持续的炎症和受损的软骨修复加速了疾病的进展。酶诱导型一氧化氮合酶（iNOS）通过产生一氧化氮（NO）促进OA，从而加剧炎症并抑制软骨再生。传统的iNOS抑制剂由于不充分的靶向释放和对炎症的不协调控制而显示出有限的疗效。在这项研究中，我们开发了一种基于dnazyme的自我支持的DNA水凝胶，使用rolling circle amplification （RCA）技术来递送靶向inos的DNAzymes和骨髓间充质干细胞衍生的外泌体（BMSC-exos），以应对炎症。该水凝胶含有甘油三酯单硬脂酸纳米颗粒（TGMS NPs），该纳米颗粒在OA关节的高基质金属蛋白酶（MMP）水平下降解，从而精确触发DNAzymes和外泌体的释放。这种靶向递送通过减少促炎NO的产生来调节炎症微环境，并通过促进M2巨噬细胞极化来支持软骨形成。体外和体内分析表明，水凝胶可显著降低炎症细胞因子水平，增强软骨细胞增殖，恢复细胞外基质完整性，最终减缓OA进展。这种智能水凝胶为微环境调节和软骨再生提供了一种有前途的双灵巧策略，有可能推进OA治疗。
{"title":"Self-supported DNA hydrogel facilitates microenvironment remodeling and cartilage repair to prevent osteoarthritis progression via an ambidextrous strategy.","authors":"Yixin Liu, Xinjian Yang, Ya Miao, Taoping Chen, Wenyan Gao, Guoqiang Zhou, Guang Jia, Xiaosong Yang, Jinchao Zhang, Yi Jin","doi":"10.1016/j.biomaterials.2025.123595","DOIUrl":"10.1016/j.biomaterials.2025.123595","url":null,"abstract":"<p><p>Osteoarthritis (OA), a prevalent degenerative joint disease, currently lacks effective therapeutic options beyond symptomatic relief. Persistent inflammation and impaired cartilage repair accelerate the disease progression. The enzyme inducible nitric oxide synthase (iNOS) contributes to OA by producing nitric oxide (NO), which intensifies inflammation and inhibits cartilage regeneration. Traditional iNOS inhibitors have demonstrated limited efficacy due to inadequate targeted release and uncoordinated control over inflammation. In this study, we developed a self-supported DNAzyme-based DNA hydrogel using rolling circle amplification (RCA) technology to deliver iNOS-targeting DNAzymes and bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) in response to inflammation. The hydrogel incorporates triglycerol monostearate nanoparticles (TGMS NPs), which degrade under high matrix metalloproteinase (MMP) levels in OA joints, thereby triggering the release of the DNAzymes and exosomes with precision. This targeted delivery modulates the inflammatory microenvironment by reducing pro-inflammatory NO production and supports chondrogenesis by promoting M2 macrophage polarization. In vitro and in vivo analyses reveal that the hydrogel significantly reduces inflammatory cytokine levels, enhances chondrocyte proliferation, and restores extracellular matrix integrity, ultimately slowing OA progression. This smart hydrogel offers a promising ambidextrous strategy for microenvironment modulation and cartilage regeneration, potentially advancing OA treatment.</p>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"325 ","pages":"123595"},"PeriodicalIF":12.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803049","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 : 2025-12-11DOI: 10.1016/j.biomaterials.2025.123905
Xiaoxia Li , Sicheng Yan , Mingding Li , Renyuan Liu , Qiangbing Lu , Minghui Lu , Feng Bai , Qun-Dong Shen
Synaptic dysfunction and loss are central drivers of cognitive decline in Alzheimer's disease (AD), yet current therapeutic approaches targeting amyloid-β or tau pathology have largely failed to rescue synaptic function. Neural oscillations and synaptic plasticity are tightly coupled and underpin functional brain networks, suggesting that modulating oscillatory dynamics may offer new therapeutic avenues. Here, we developed a strategy for precise, non-genetic neuromodulation using focused ultrasound and piezoelectric Ba0.85Ca0.15Zr0.1Ti0.9O3 (BCZT) nanoparticles to generate targeted, gamma-frequency electromagnetic fields in the hippocampal CA3 subregion of early-stage AD mouse models. This rhythmic stimulation effectively restored impaired gamma oscillations, enhanced synaptic plasticity, and remodeled memory-related network connectivity, as validated by local field potential recordings, patch-clamp electrophysiology, and functional MRI. Mechanistically, we demonstrate that NF-κB transcription factor activation during rhythmic stimulation regulates AMPAR trafficking by balancing synaptic internalization and delivery, with concurrent upregulation of P300-mediated histone acetylation. Our findings establish a novel paradigm for spatially precise, periodic neuromodulation that restores hippocampal information processing and network function in early AD, highlighting the therapeutic potential of piezoelectric nanomaterials for neural circuit repair in AD and other neurodegenerative diseases characterized by impaired neural rhythms.
{"title":"Piezoelectric nanoparticle-driven rhythmic ultrasound neuromodulation for treatment of early-stage Alzheimer's disease","authors":"Xiaoxia Li , Sicheng Yan , Mingding Li , Renyuan Liu , Qiangbing Lu , Minghui Lu , Feng Bai , Qun-Dong Shen","doi":"10.1016/j.biomaterials.2025.123905","DOIUrl":"10.1016/j.biomaterials.2025.123905","url":null,"abstract":"<div><div>Synaptic dysfunction and loss are central drivers of cognitive decline in Alzheimer's disease (AD), yet current therapeutic approaches targeting amyloid-β or tau pathology have largely failed to rescue synaptic function. Neural oscillations and synaptic plasticity are tightly coupled and underpin functional brain networks, suggesting that modulating oscillatory dynamics may offer new therapeutic avenues. Here, we developed a strategy for precise, non-genetic neuromodulation using focused ultrasound and piezoelectric Ba<sub>0.85</sub>Ca<sub>0.15</sub>Zr<sub>0.1</sub>Ti<sub>0.9</sub>O<sub>3</sub> (BCZT) nanoparticles to generate targeted, gamma-frequency electromagnetic fields in the hippocampal CA3 subregion of early-stage AD mouse models. This rhythmic stimulation effectively restored impaired gamma oscillations, enhanced synaptic plasticity, and remodeled memory-related network connectivity, as validated by local field potential recordings, patch-clamp electrophysiology, and functional MRI. Mechanistically, we demonstrate that NF-κB transcription factor activation during rhythmic stimulation regulates AMPAR trafficking by balancing synaptic internalization and delivery, with concurrent upregulation of P300-mediated histone acetylation. Our findings establish a novel paradigm for spatially precise, periodic neuromodulation that restores hippocampal information processing and network function in early AD, highlighting the therapeutic potential of piezoelectric nanomaterials for neural circuit repair in AD and other neurodegenerative diseases characterized by impaired neural rhythms.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123905"},"PeriodicalIF":12.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732906","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 : 2025-12-11DOI: 10.1016/j.biomaterials.2025.123901
Jie Zou , Guilin Meng , Yiming Huang , Jiangyan Huo , Hang Yuan , Huihui Ma , Zhi You , Xiaoli Yan , Bing Shen , Min Zhang , Yannan Yang
Manganese (Mn2+) serves as an inorganic activator of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. However, its activation efficiency remains lower than conventional organic STING agonists, hindering widespread applications in immune modulation and therapy. Herein, we report an intermediate-crystalline phase manganese layered double hydroxide/oxide (Mn-LDH/O150) nanocomposite, featuring both LDH and LDO structural phases, as a potent cGAS-STING activator. Surprisingly, Mn-LDH/O150 induced a type-I interferon level significantly higher than pure Mn-LDH or LDO phase nanocomposites, and comparable to organic STING agonists (cGAMP/diABZI). Mechanistically, conventional Mn nanocomposite impairs energy metabolism in dendritic cells and significantly reduces mitochondrial ATP production. In contrast, Mn-LDH/O150 modulates mitochondrial metabolism by normalizing the electron transport chain (ETC) process, which is termed “immunometabolism normalization”, thereby promoting ATP production that in turn facilitates cGAMP synthesis and STING activation. In mice models, Mn-LDH/O150 acts as a potent immune adjuvant in inducing antibodies production and T cell responses. Using a model antigen (ovalbumin) and melanoma neoantigens, we further demonstrate the excellent activity of Mn-LDH/O150-based vaccine in inducing antitumor immunity to prevent tumor progression and metastasis. Our discoveries highlight the crucial involvement of energy metabolism in modulating STING activation, and present a simple yet translational material engineering approach for boosting metalloimmunotherapy.
{"title":"An intermediate-crystalline phase manganese nanoadjuvant potently activates cGAS-STING signaling and antitumor immunity via immunometabolism normalization","authors":"Jie Zou , Guilin Meng , Yiming Huang , Jiangyan Huo , Hang Yuan , Huihui Ma , Zhi You , Xiaoli Yan , Bing Shen , Min Zhang , Yannan Yang","doi":"10.1016/j.biomaterials.2025.123901","DOIUrl":"10.1016/j.biomaterials.2025.123901","url":null,"abstract":"<div><div>Manganese (Mn<sup>2+</sup>) serves as an inorganic activator of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. However, its activation efficiency remains lower than conventional organic STING agonists, hindering widespread applications in immune modulation and therapy. Herein, we report an intermediate-crystalline phase manganese layered double hydroxide/oxide (Mn-LDH/O<sub>150</sub>) nanocomposite, featuring both LDH and LDO structural phases, as a potent cGAS-STING activator. Surprisingly, Mn-LDH/O<sub>150</sub> induced a type-I interferon level significantly higher than pure Mn-LDH or LDO phase nanocomposites, and comparable to organic STING agonists (cGAMP/diABZI). Mechanistically, conventional Mn nanocomposite impairs energy metabolism in dendritic cells and significantly reduces mitochondrial ATP production. In contrast, Mn-LDH/O<sub>150</sub> modulates mitochondrial metabolism by normalizing the electron transport chain (ETC) process, which is termed “immunometabolism normalization”, thereby promoting ATP production that in turn facilitates cGAMP synthesis and STING activation. In mice models, Mn-LDH/O<sub>150</sub> acts as a potent immune adjuvant in inducing antibodies production and T cell responses. Using a model antigen (ovalbumin) and melanoma neoantigens, we further demonstrate the excellent activity of Mn-LDH/O<sub>150</sub>-based vaccine in inducing antitumor immunity to prevent tumor progression and metastasis. Our discoveries highlight the crucial involvement of energy metabolism in modulating STING activation, and present a simple yet translational material engineering approach for boosting metalloimmunotherapy.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123901"},"PeriodicalIF":12.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732907","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 : 2025-12-06DOI: 10.1016/j.biomaterials.2025.123897
Jianming Zhang , Haoran Liu , Chao Li , Lei Yue , Qilong Wang , Xingzhe Yu , Xingsheng Zhang , Changsheng Huang , Shaohuang Liu , Ziqi Wang , Cong Lei , Zhangzheng Liao , Ranlyu Zhu , Lei Yang , Haolin Sun
This study assessed the use of injectable calcium phosphate nanocomposite (CPN) for enhancing spinal screw fixation in a sheep model for osteoporosis, with the aim of addressing the limitations of polymethyl methacrylate(PMMA) and calcium phosphate cement(CPC). In vitro, CPN showed superior compressive strength (58.2 MPa vs. 15.0 MPa for CPC) and modulus (2.6 GPa vs. 1.51 GPa for PMMA), with favorable injectability and degradation. In the osteoporosis sheep model (induced via ovariectomy and methylprednisolone), CPN-augmented screws exhibited enhanced static mechanical performance (pull-out force, torque) at 12 weeks, surpassing that of PMMA and CPC, with comparable short-term fatigue durability to PMMA and better long-term residual stability. Micro-CT and histology confirmed that CPN promoted more new bone formation (BV/TV: 56.1 % at 12 weeks) and bone-implant contact (78.1 % at 12 weeks) via synergistic degradation and osteogenesis. Biosafety was validated by the absence of organ damage and abnormal blood parameters. These results indicate that CPN balances immediate mechanical support and long-term biological adaptation, yielding promising findings for application in spinal fixation for patients with osteoporosis.
本研究评估了可注射磷酸钙纳米复合材料（CPN）在骨质疏松羊模型中增强脊柱螺钉固定的应用，旨在解决聚甲基丙烯酸甲酯（PMMA）和磷酸钙水泥（CPC）的局限性。在体外，CPN具有优越的抗压强度（58.2 MPa vs. 15.0 MPa CPC）和模量（2.6 GPa vs. 1.51 GPa PMMA），具有良好的注射性和降解性。在骨质疏松羊模型（通过卵巢切除和甲基强的松龙诱导）中，cpn增强螺钉在12周时表现出增强的静态力学性能（拔出力，扭矩），超过PMMA和CPC，具有与PMMA相当的短期疲劳耐久性和更好的长期残余稳定性。显微ct和组织学证实，CPN通过协同降解和成骨促进了更多的新骨形成（12周时BV/TV: 56.1%）和骨-种植体接触（12周时78.1%）。通过无器官损伤和血液参数异常验证了生物安全性。这些结果表明，CPN平衡了即时机械支持和长期生物适应，为骨质疏松症患者脊柱固定的应用带来了有希望的发现。
{"title":"Injectable Calcium Phosphate Nanocomposite: Balancing Mechanical Support and Osseointegration for Enhanced Spinal Screw Fixation in an Osteoporosis Sheep Model","authors":"Jianming Zhang , Haoran Liu , Chao Li , Lei Yue , Qilong Wang , Xingzhe Yu , Xingsheng Zhang , Changsheng Huang , Shaohuang Liu , Ziqi Wang , Cong Lei , Zhangzheng Liao , Ranlyu Zhu , Lei Yang , Haolin Sun","doi":"10.1016/j.biomaterials.2025.123897","DOIUrl":"10.1016/j.biomaterials.2025.123897","url":null,"abstract":"<div><div>This study assessed the use of injectable calcium phosphate nanocomposite (CPN) for enhancing spinal screw fixation in a sheep model for osteoporosis, with the aim of addressing the limitations of polymethyl methacrylate(PMMA) and calcium phosphate cement(CPC). <em>In vitro</em>, CPN showed superior compressive strength (58.2 MPa <em>vs.</em> 15.0 MPa for CPC) and modulus (2.6 GPa <em>vs.</em> 1.51 GPa for PMMA), with favorable injectability and degradation. In the osteoporosis sheep model (induced via ovariectomy and methylprednisolone), CPN-augmented screws exhibited enhanced static mechanical performance (pull-out force, torque) at 12 weeks, surpassing that of PMMA and CPC, with comparable short-term fatigue durability to PMMA and better long-term residual stability. Micro-CT and histology confirmed that CPN promoted more new bone formation (BV/TV: 56.1 % at 12 weeks) and bone-implant contact (78.1 % at 12 weeks) via synergistic degradation and osteogenesis. Biosafety was validated by the absence of organ damage and abnormal blood parameters. These results indicate that CPN balances immediate mechanical support and long-term biological adaptation, yielding promising findings for application in spinal fixation for patients with osteoporosis.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123897"},"PeriodicalIF":12.9,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712759","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 : 2025-12-05DOI: 10.1016/j.biomaterials.2025.123896
Qiuxia Luo , Ye Tong , Xue Li , Zhijun Zhang , Yi Qin , Dong Wang , Ben Zhong Tang
Covalent organic frameworks (COFs) are promising materials for cancer phototherapy, however, achieving precise multimodal theranostics in deep tissues remains challenging due to their typically short emission wavelengths. To address this limitation, we developed for the first time a COF with second near-infrared aggregation-induced emission (NIR-II AIE) characteristics, termed COF-AIE, by noncovalently incorporating the NIR-II AIE-active molecule BTT-COOH into TB-COF. COF-AIE exhibits an emission peak at ∼1000 nm, demonstrating exceptional NIR-II AIE properties. Importantly, the confinement of BTT-COOH within the COF framework affords the enhanced NIR-II fluorescence intensity compared to free BTT-COOH. Beyond that, COF-AIE retains the excellent photothermal conversion efficiency of BTT-COOH, while its high porosity promotes oxygen diffusion, boosting reactive oxygen species generation. These synergistic enhancements were further corroborated by density functional theory calculations. By integrating multiple optimized properties, COF-AIE achieves outstanding performance in NIR-II fluorescence imaging-navigated photothermal-photodynamic synergistic therapy towards tumor.
{"title":"Covalent organic framework with second near-infrared aggregation-induced emission for boosted tumor multimodal phototheranostics","authors":"Qiuxia Luo , Ye Tong , Xue Li , Zhijun Zhang , Yi Qin , Dong Wang , Ben Zhong Tang","doi":"10.1016/j.biomaterials.2025.123896","DOIUrl":"10.1016/j.biomaterials.2025.123896","url":null,"abstract":"<div><div>Covalent organic frameworks (COFs) are promising materials for cancer phototherapy, however, achieving precise multimodal theranostics in deep tissues remains challenging due to their typically short emission wavelengths. To address this limitation, we developed for the first time a COF with second near-infrared aggregation-induced emission (NIR-II AIE) characteristics, termed COF-AIE, by noncovalently incorporating the NIR-II AIE-active molecule BTT-COOH into TB-COF. COF-AIE exhibits an emission peak at ∼1000 nm, demonstrating exceptional NIR-II AIE properties. Importantly, the confinement of BTT-COOH within the COF framework affords the enhanced NIR-II fluorescence intensity compared to free BTT-COOH. Beyond that, COF-AIE retains the excellent photothermal conversion efficiency of BTT-COOH, while its high porosity promotes oxygen diffusion, boosting reactive oxygen species generation. These synergistic enhancements were further corroborated by density functional theory calculations. By integrating multiple optimized properties, COF-AIE achieves outstanding performance in NIR-II fluorescence imaging-navigated photothermal-photodynamic synergistic therapy towards tumor.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123896"},"PeriodicalIF":12.9,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712926","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 : 2025-12-04DOI: 10.1016/j.biomaterials.2025.123894
Derui Xu , Tong Xu , Yunxiang Zhang , Yanjun Su , Xinmiao Hou , Yating Cui , Qian Liu , Lingxia Liu , Xiaotao Zhou , Haixu Xu , Xinghua Jin , Xichuan Li
Tumor immune microenvironment reconstruction and regulated cell death promotion synergistically enhance treatment outcomes in immunosuppressive non-small-cell lung cancer (NSCLC). PANoptosis, a newly identified form of immunogenic cell death that integrates the essential molecular components of pyroptosis, apoptosis, and necroptosis, elicits robust antitumor immunity via damage-associated molecular pattern (DAMP)-mediated immune activation. Nevertheless, strategies to induce PANoptosis remain underexplored, presenting a critical gap in leveraging its therapeutic potential. Herein, we engineered a multifunctional nanoreactor (Bi@SiO2@COP@AQ4N&PTX@hybrid-membrane, BSCAPM) as a PANoptosis inducer by integrating photothermal, photodynamic, chemotherapy, and SiO2-mediated biological effects. The nanoreactor features a bismuth-based core for photothermal functionality, in conjunction with a SiO2 layer and a drug-loaded covalent organic polymer (COP) nanoplatform that synergistically disrupts mitochondrial homeostasis. In addition, the bioactive nanoparticles mediate co-delivery of paclitaxel and phenoxyanthraquinone, concurrently compromising nuclear DNA superhelical integrity and triggering profound mitochondrial stress culminating in PANoptosome assembly and ZBP1-dependent PANoptosis. In vitro and in vivo studies demonstrated that BSCAPM effectively targeted tumor sites, initiated ZBP1-dependent PANoptosis and elicited a robust immunogenic response, leading to enhanced tumor elimination and lung metastasis restraints. This study not only elucidates the mechanistic basis of BSCAPM-induced PANoptosis but also provides a new strategy for the precise treatment of NSCLC.
{"title":"Nanoreactor-enabled PANoptosis via ZBP1 activation potentiates immunotherapy in non-small cell lung cancer","authors":"Derui Xu , Tong Xu , Yunxiang Zhang , Yanjun Su , Xinmiao Hou , Yating Cui , Qian Liu , Lingxia Liu , Xiaotao Zhou , Haixu Xu , Xinghua Jin , Xichuan Li","doi":"10.1016/j.biomaterials.2025.123894","DOIUrl":"10.1016/j.biomaterials.2025.123894","url":null,"abstract":"<div><div><em>Tumor immune</em> microenvironment reconstruction and regulated cell death promotion synergistically enhance treatment outcomes in immunosuppressive non-small-cell lung cancer (NSCLC). PANoptosis, a newly identified form of immunogenic cell death that integrates the essential molecular components of pyroptosis, apoptosis, and necroptosis, elicits robust antitumor immunity via damage-associated molecular pattern (DAMP)-mediated immune activation. Nevertheless, strategies to induce PANoptosis remain underexplored, presenting a critical gap in leveraging its therapeutic potential. Herein, we engineered a multifunctional nanoreactor (Bi@SiO<sub>2</sub>@COP@AQ4N&PTX@hybrid-membrane, BSCAPM) as a PANoptosis inducer by integrating photothermal, photodynamic, chemotherapy, and SiO<sub>2</sub>-mediated biological effects. The nanoreactor features a bismuth-based core for photothermal functionality, in conjunction with a SiO<sub>2</sub> layer and a drug-loaded covalent organic polymer (COP) nanoplatform that synergistically disrupts mitochondrial homeostasis. In addition, the bioactive nanoparticles mediate co-delivery of paclitaxel and phenoxyanthraquinone, concurrently compromising nuclear DNA superhelical integrity and triggering profound mitochondrial stress culminating in PANoptosome assembly and ZBP1-dependent PANoptosis. <em>In vitro</em> and <em>in vivo</em> studies demonstrated that BSCAPM effectively targeted tumor sites, initiated ZBP1-dependent PANoptosis and elicited a robust immunogenic response, leading to enhanced tumor elimination and lung metastasis restraints. This study not only elucidates the mechanistic basis of BSCAPM-induced PANoptosis but also provides a new strategy for the precise treatment of NSCLC.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123894"},"PeriodicalIF":12.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712749","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 : 2025-12-04DOI: 10.1016/j.biomaterials.2025.123890
Bing Ye , Huiling Lei , Xirui Jing , Qiuyue Ding , Sheng Yao , Hong Wang , Chunqing Meng , Xiaodong Guo , Bin Wu , Yuzhou Wu , Tingfang Sun
Vascularization-ossification coupling is pivotal for bone defect repair. Neovascularization guides the migration of osteogenic precursor cells, and osteoblasts in the perivascular area support vascular regeneration through the secretion of cytokines. Delivery systems are being engineered to orchestrate the coupling of vascularization and ossification precisely. However, most delivery systems lack sensitivity to the inherent repair environment, hampering timely bone formation. This study developed a vascular environment-responsive biomaterial: a true bone ceramic/small intestine submucosa (TBC/SIS) scaffold loaded with nanoswitch and Apt19s-functionalized nanoparticles. This scaffold is designed to release the functionalized nanoparticles via an “unfolding–refolding” nanoswitch based on base pairing and protein-nucleic acid recognition. The TBC/SIS scaffold initiates neovascularization, prompting endothelial cells to secrete nucleolin. The nanoswitches detect nucleolin and trigger the release of nanoparticles, thereby creating a responsive vascular environment. Moreover, when modified with aptamer-19s, the nanoparticles can attract mesenchymal stem cells to perivascular areas, facilitating spatial coupling with blood vessels. Encapsulating miR-26a in nanoparticles enhances osteogenic activity and stimulates the secretion of vascular endothelial growth factor. As vascular endothelial cells infiltrate, nanoparticles are continuously released from the scaffold, establishing a positive feedback loop that promotes vascularization-ossification coupling and ultimately enhances bone regeneration. Our findings provide valuable insights for designing intelligent materials that utilize endogenous stimuli to enhance spatiotemporal interactions between vascularization and ossification. Further in-depth studies on the expression of nucleolin in vivo will continue to refine this promising strategy.
{"title":"Vascular environment-responsive DNA nanoswitch controls the positive feedback system for spatiotemporal coupling of angiogenesis and osteogenesis","authors":"Bing Ye , Huiling Lei , Xirui Jing , Qiuyue Ding , Sheng Yao , Hong Wang , Chunqing Meng , Xiaodong Guo , Bin Wu , Yuzhou Wu , Tingfang Sun","doi":"10.1016/j.biomaterials.2025.123890","DOIUrl":"10.1016/j.biomaterials.2025.123890","url":null,"abstract":"<div><div>Vascularization-ossification coupling is pivotal for bone defect repair. Neovascularization guides the migration of osteogenic precursor cells, and osteoblasts in the perivascular area support vascular regeneration through the secretion of cytokines. Delivery systems are being engineered to orchestrate the coupling of vascularization and ossification precisely. However, most delivery systems lack sensitivity to the inherent repair environment, hampering timely bone formation. This study developed a vascular environment-responsive biomaterial: a true bone ceramic/small intestine submucosa (TBC/SIS) scaffold loaded with nanoswitch and Apt19s-functionalized nanoparticles. This scaffold is designed to release the functionalized nanoparticles via an “unfolding–refolding” nanoswitch based on base pairing and protein-nucleic acid recognition. The TBC/SIS scaffold initiates neovascularization, prompting endothelial cells to secrete nucleolin. The nanoswitches detect nucleolin and trigger the release of nanoparticles, thereby creating a responsive vascular environment. Moreover, when modified with aptamer-19s, the nanoparticles can attract mesenchymal stem cells to perivascular areas, facilitating spatial coupling with blood vessels. Encapsulating miR-26a in nanoparticles enhances osteogenic activity and stimulates the secretion of vascular endothelial growth factor. As vascular endothelial cells infiltrate, nanoparticles are continuously released from the scaffold, establishing a positive feedback loop that promotes vascularization-ossification coupling and ultimately enhances bone regeneration. Our findings provide valuable insights for designing intelligent materials that utilize endogenous stimuli to enhance spatiotemporal interactions between vascularization and ossification. Further in-depth studies on the expression of nucleolin in vivo will continue to refine this promising strategy.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123890"},"PeriodicalIF":12.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712686","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 : 2025-12-04DOI: 10.1016/j.biomaterials.2025.123889
Deepak A. Subramanian , Ameya R. Kirtane , Georgia N. White , Dylan E. Freitas , Keiko Ishida , Josh Jenkins , Andrew Pettinari , Josh Morimoto , Nina Fitzgerald , Giovanni Traverso
Oral drug delivery is a widely used method of drug administration; however, achieving localized drug release at specific regions of the gastrointestinal (GI) tract is generally accomplished by using broad environmental differences. The GI tract is a complex system with regional differences in composition, such as selective expression of mucin glycoproteins in different organs. Here, we identify small molecule ligands that can selectively bind to the different mucins to localize drug delivery to the small intestine and stomach. We demonstrate up to a 10-fold increase in particle binding to these organs and up to a 4-fold increase in selectivity compared to chitosan. Additionally, we observe up to a 9-fold increase in budesonide concentration in the small intestine and a 25-fold increase in tetracycline concentration in the stomach. These results show that we have developed a versatile platform capable of sequestering a variety of drugs in certain GI tract organs.
{"title":"Identification and validation of small molecules with mucin-selective regiospecific binding in the gastrointestinal tract","authors":"Deepak A. Subramanian , Ameya R. Kirtane , Georgia N. White , Dylan E. Freitas , Keiko Ishida , Josh Jenkins , Andrew Pettinari , Josh Morimoto , Nina Fitzgerald , Giovanni Traverso","doi":"10.1016/j.biomaterials.2025.123889","DOIUrl":"10.1016/j.biomaterials.2025.123889","url":null,"abstract":"<div><div>Oral drug delivery is a widely used method of drug administration; however, achieving localized drug release at specific regions of the gastrointestinal (GI) tract is generally accomplished by using broad environmental differences. The GI tract is a complex system with regional differences in composition, such as selective expression of mucin glycoproteins in different organs. Here, we identify small molecule ligands that can selectively bind to the different mucins to localize drug delivery to the small intestine and stomach. We demonstrate up to a 10-fold increase in particle binding to these organs and up to a 4-fold increase in selectivity compared to chitosan. Additionally, we observe up to a 9-fold increase in budesonide concentration in the small intestine and a 25-fold increase in tetracycline concentration in the stomach. These results show that we have developed a versatile platform capable of sequestering a variety of drugs in certain GI tract organs.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"328 ","pages":"Article 123889"},"PeriodicalIF":12.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732919","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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