Pub Date : 2026-07-01Epub Date: 2026-01-14DOI: 10.1016/j.biomaterials.2026.124000
Nivethika Sivakumaran , Joseph Freitas , Shuxiong Chen , Alfred K. Lam , Lucas J. Adams , Michael S. Diamond , Suresh Mahalingam , Bernd H.A. Rehm
Chikungunya virus, a mosquito-borne alphavirus, causes outbreaks of both acute and chronic musculoskeletal diseases. Despite the recent approval of a live-attenuated and virus-like particle-based vaccine, a stable, safe and efficacious vaccine that can be manufactured at low cost is lacking. To address this need, we engineered Escherichia coli to produce robust biopolymer particles (BPs) densely coated with CHIKV envelope glycoproteins E2 and E1, forming a natively folded heterodimer mimicking the virus surface (E2-BP-E1). Native E2-E1 heterodimer formation was confirmed by monoclonal antibodies binding to five neutralizing epitopes and by binding of the receptor Mxra8. The structural model of BP-tethered E2-E1 aligned with the crystal structure of mature E2-E1 complex. In vitro, E2-BP-E1 activated dendritic cells (DCs) to produce Th1 cytokines, present MHC class I/II T cell epitopes, and stimulate CD4+ and CD8+ T cell proliferation. In vivo, vaccination without adjuvant induced potent neutralizing antibodies and protective immunity, with a ∼5 log10 reduction in viremia. Histological analysis of muscle and joints confirmed reduced inflammation and pathology in vaccinated mice. E2-BP-E1 was produced using standard E. coli fermentation suggesting safe, cost-effective and scalable manufacturability offering advantages over current vaccines. Overall, we developed a stable particulate CHIKV vaccine that is safe and efficiently protects against infection without the need of an adjuvant.
基孔肯雅病毒是一种蚊媒甲病毒，可引起急性和慢性肌肉骨骼疾病的暴发。尽管最近批准了一种减毒活疫苗和病毒样颗粒疫苗，但缺乏一种稳定、安全、有效、可低成本生产的疫苗。为了满足这一需求，我们对大肠杆菌进行了改造，使其产生强大的生物聚合物颗粒（bp），这些生物聚合物颗粒被CHIKV包膜糖蛋白E2和E1密集包裹，形成一个天然折叠的异二聚体，模拟病毒表面（E2- bp -E1）。通过与5个中和表位结合的单克隆抗体和与受体Mxra8结合，证实了天然E2-E1异二聚体的形成。bp拴链E2-E1的结构模型与成熟E2-E1配合物的晶体结构一致。在体外，E2-BP-E1激活树突状细胞（dc）产生Th1细胞因子，呈现MHC类I/II T细胞表位，并刺激CD4+和CD8+ T细胞增殖。在体内，无佐剂的疫苗接种诱导了有效的中和抗体和保护性免疫，病毒血症减少了约5 log10。肌肉和关节的组织学分析证实，接种疫苗的小鼠炎症和病理减少。E2-BP-E1采用标准大肠杆菌发酵生产，与目前的疫苗相比，具有安全性、成本效益和可规模化生产的优势。总的来说，我们开发了一种稳定的颗粒状CHIKV疫苗，它安全有效地防止感染，而不需要佐剂。
{"title":"Adjuvant-free biopolymer particles mimicking the Chikungunya virus surface induce protective immunity","authors":"Nivethika Sivakumaran , Joseph Freitas , Shuxiong Chen , Alfred K. Lam , Lucas J. Adams , Michael S. Diamond , Suresh Mahalingam , Bernd H.A. Rehm","doi":"10.1016/j.biomaterials.2026.124000","DOIUrl":"10.1016/j.biomaterials.2026.124000","url":null,"abstract":"<div><div>Chikungunya virus, a mosquito-borne alphavirus, causes outbreaks of both acute and chronic musculoskeletal diseases. Despite the recent approval of a live-attenuated and virus-like particle-based vaccine, a stable, safe and efficacious vaccine that can be manufactured at low cost is lacking. To address this need, we engineered <em>Escherichia coli</em> to produce robust biopolymer particles (BPs) densely coated with CHIKV envelope glycoproteins E2 and E1, forming a natively folded heterodimer mimicking the virus surface (E2-BP-E1). Native E2-E1 heterodimer formation was confirmed by monoclonal antibodies binding to five neutralizing epitopes and by binding of the receptor Mxra8. The structural model of BP-tethered E2-E1 aligned with the crystal structure of mature E2-E1 complex. <em>In vitro</em>, E2-BP-E1 activated dendritic cells (DCs) to produce Th1 cytokines, present MHC class I/II T cell epitopes, and stimulate CD4<sup>+</sup> and CD8<sup>+</sup> T cell proliferation. <em>In vivo</em>, vaccination without adjuvant induced potent neutralizing antibodies and protective immunity, with a ∼5 log<sub>10</sub> reduction in viremia. Histological analysis of muscle and joints confirmed reduced inflammation and pathology in vaccinated mice. E2-BP-E1 was produced using standard <em>E. coli</em> fermentation suggesting safe, cost-effective and scalable manufacturability offering advantages over current vaccines. Overall, we developed a stable particulate CHIKV vaccine that is safe and efficiently protects against infection without the need of an adjuvant.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124000"},"PeriodicalIF":12.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016724","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 : 2026-07-01Epub Date: 2026-01-17DOI: 10.1016/j.biomaterials.2026.124006
Xuehao Tian , Yuting Wen , Zhongxing Zhang , Ke Zhou , Lu Shang , Jingling Zhu , Xia Song , Jun Li
Diabetic wounds present a significant clinical challenge due to prolonged inflammation and impaired healing associated with excessive reactive oxygen species (ROS) and macrophage dysfunction. In this study, we developed a smart multifunctional ROS-responsive supramolecular hydrogel composed of carboxymethyl chitosan (CMCS) that is dynamically crosslinked by inclusion complexes of β-cyclodextrin (βCD) and ferrocene (Fc). This hydrogel facilitates the on-demand release of interleukin-4 (IL-4) while exhibiting intrinsic antibacterial properties. The IL-4-loaded hydrogel (IL-4@Gel-CD/Fc) responds to elevated H2O2 levels, destabilizing βCD/Fc crosslinking through the Fenton reaction, which simultaneously promotes ROS scavenging and accelerates IL-4 release. The system subsequently reprograms macrophages from the proinflammatory M1 phenotype to the anti‒inflammatory M2 phenotype, thereby addressing immune dysregulation in diabetic wounds. In vitro evaluations demonstrated significant reductions in ROS levels, effective M2 macrophage polarization, and antibacterial activity. In vivo studies using a diabetic rat model revealed that, compared to controls, IL-4@Gel-CD/Fc significantly enhanced wound closure, collagen density, and angiogenesis while reducing proinflammatory cytokines (IL-6 and TNF-α) and increasing anti‒inflammatory cytokine IL-10 levels. Overall, this smart hydrogel system offers a novel strategy to simultaneously regulate oxidative stress, immune dysregulation, and bacterial infection, thereby promoting effective wound healing in diabetic conditions.
{"title":"Smart multifunctional ROS-responsive supramolecular hydrogel for simultaneously regulating oxidative stress, immune dysregulation, and bacterial infection in diabetic wound healing","authors":"Xuehao Tian , Yuting Wen , Zhongxing Zhang , Ke Zhou , Lu Shang , Jingling Zhu , Xia Song , Jun Li","doi":"10.1016/j.biomaterials.2026.124006","DOIUrl":"10.1016/j.biomaterials.2026.124006","url":null,"abstract":"<div><div>Diabetic wounds present a significant clinical challenge due to prolonged inflammation and impaired healing associated with excessive reactive oxygen species (ROS) and macrophage dysfunction. In this study, we developed a smart multifunctional ROS-responsive supramolecular hydrogel composed of carboxymethyl chitosan (CMCS) that is dynamically crosslinked by inclusion complexes of β-cyclodextrin (βCD) and ferrocene (Fc). This hydrogel facilitates the on-demand release of interleukin-4 (IL-4) while exhibiting intrinsic antibacterial properties. The IL-4-loaded hydrogel (IL-4@Gel-CD/Fc) responds to elevated H<sub>2</sub>O<sub>2</sub> levels, destabilizing βCD/Fc crosslinking through the Fenton reaction, which simultaneously promotes ROS scavenging and accelerates IL-4 release. The system subsequently reprograms macrophages from the proinflammatory M1 phenotype to the anti‒inflammatory M2 phenotype, thereby addressing immune dysregulation in diabetic wounds. In vitro evaluations demonstrated significant reductions in ROS levels, effective M2 macrophage polarization, and antibacterial activity. In vivo studies using a diabetic rat model revealed that, compared to controls, IL-4@Gel-CD/Fc significantly enhanced wound closure, collagen density, and angiogenesis while reducing proinflammatory cytokines (IL-6 and TNF-α) and increasing anti‒inflammatory cytokine IL-10 levels. Overall, this smart hydrogel system offers a novel strategy to simultaneously regulate oxidative stress, immune dysregulation, and bacterial infection, thereby promoting effective wound healing in diabetic conditions.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124006"},"PeriodicalIF":12.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024839","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 : 2026-07-01Epub Date: 2026-01-29DOI: 10.1016/j.biomaterials.2026.124031
George Ronan , Lauren Hawthorne , Jun Yang , Ruyu Zhou , Frank Ketchum , Nicole Kowalczyk , Fang Liu , Pinar Zorlutuna
Aging is a major risk factor for cardiovascular disease, the leading cause of death worldwide, and numerous other diseases, but the mechanisms of these aging-related effects remain elusive. Recent evidence suggests that chronic changes in the microenvironment and local paracrine signaling are major drivers of these effects, but the precise effect of aging on these factors remains understudied. Here, for the first time, we directly compare extracellular vesicles obtained from young and aged patients to identify therapeutic or disease-associated agents, and directly compare vesicles isolated from heart tissue matrix (TEVs) or plasma (PEVs). While young TEVs and PEVs showed notable overlap of miRNA cargo, aged EVs differed substantially, indicating differential aging-related changes between TEVs and PEVs. TEVs overall were uniquely enriched in miRNAs which directly or indirectly demonstrate cardioprotective effects, with 45 potential therapeutic agents identified in our analysis. Both populations also showed increased predisposition to disease with aging, though through different mechanisms. Changes in PEV cargo were largely correlated with chronic systemic inflammation, while those in TEVs were more related to cardiac homeostasis and local inflammation. From this, 17 protein targets were identified which were unique to TEVs and highly correlated with aging and the onset of cardiovascular disease. Further analysis via machine learning techniques implicated several new miRNA and protein targets, independently suggesting several of the targets identified by non-machine learning analysis, which correlated with aging-related changes in TEVs. With further study, this biomarker set may serve as a powerful, potential indicator of cardiac health and age which can be measured from PEVs. Additionally, several proposed “young-enriched” therapeutic agents were validated and, when tested, could successfully prevent cell death and cardiac fibrosis in disease-like conditions using a microfluidic heart-on-a-chip to model of acute and chronic fibrosis, making this study the first in literature to test the efficacy of a miRNA-based therapeutic encapsulated in lipid nanoparticles in an organ-on-a-chip device.
{"title":"“Comprehensive multi-omics of age-respective plasma and matrix-bound extracellular vesicles identifies anti-fibrotic miRNAs validated on a heart-on-a-chip”","authors":"George Ronan , Lauren Hawthorne , Jun Yang , Ruyu Zhou , Frank Ketchum , Nicole Kowalczyk , Fang Liu , Pinar Zorlutuna","doi":"10.1016/j.biomaterials.2026.124031","DOIUrl":"10.1016/j.biomaterials.2026.124031","url":null,"abstract":"<div><div>Aging is a major risk factor for cardiovascular disease, the leading cause of death worldwide, and numerous other diseases, but the mechanisms of these aging-related effects remain elusive. Recent evidence suggests that chronic changes in the microenvironment and local paracrine signaling are major drivers of these effects, but the precise effect of aging on these factors remains understudied. Here, for the first time, we directly compare extracellular vesicles obtained from young and aged patients to identify therapeutic or disease-associated agents, and directly compare vesicles isolated from heart tissue matrix (TEVs) or plasma (PEVs). While young TEVs and PEVs showed notable overlap of miRNA cargo, aged EVs differed substantially, indicating differential aging-related changes between TEVs and PEVs. TEVs overall were uniquely enriched in miRNAs which directly or indirectly demonstrate cardioprotective effects, with 45 potential therapeutic agents identified in our analysis. Both populations also showed increased predisposition to disease with aging, though through different mechanisms. Changes in PEV cargo were largely correlated with chronic systemic inflammation, while those in TEVs were more related to cardiac homeostasis and local inflammation. From this, 17 protein targets were identified which were unique to TEVs and highly correlated with aging and the onset of cardiovascular disease. Further analysis via machine learning techniques implicated several new miRNA and protein targets, independently suggesting several of the targets identified by non-machine learning analysis, which correlated with aging-related changes in TEVs. With further study, this biomarker set may serve as a powerful, potential indicator of cardiac health and age which can be measured from PEVs. Additionally, several proposed “young-enriched” therapeutic agents were validated and, when tested, could successfully prevent cell death and cardiac fibrosis in disease-like conditions using a microfluidic heart-on-a-chip to model of acute and chronic fibrosis, making this study the first in literature to test the efficacy of a miRNA-based therapeutic encapsulated in lipid nanoparticles in an organ-on-a-chip device.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124031"},"PeriodicalIF":12.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075288","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 : 2026-07-01Epub Date: 2026-01-07DOI: 10.1016/j.biomaterials.2025.123968
Yongchang Tian , Rong Zhang , Xingjun Zhao , Ian W. Hamley , Chunsheng Xiao , Li Chen
Antimicrobial hydrogels that can effectively eliminate microorganisms to accelerate wound healing have demostrated great potential in managing wound infections. However, conventional hydrogel dressings have limited contact with bacteria due to their permemnent cross-linked structure, thereby reducing their bactericidal efficiency. To address this issue, we designed and prepared a neutrophil extracellular traps (NETs) biomimetic antibacterial hydrogel (PETP gel) with enhanced bacteria contact and bactericidal efficiency through Schiff base crosslinking of antibacterial polymer PETP-NH2 and phenylboronic acid functionalized oxidized hyaluronic acid (OHA-PBA). The obtained PETP gel exhibited a NETs-mimicking dynamic filamentous network structure, which, in combination with the interaction between phenylboronic acid in OHA-PBA and lipopolysaccharides in bacterial surface, ultimately led to enhanced bacteria contact and bactericidal efficiency. In vivo experiments showed that PETP gel could accelerate healing in treatment of purulent subcutaneous infection, full-thickness wound infection, and deep second-degree burn infection, showing promising use as an antibacterial care dressing.
{"title":"A biomietic filamentous hydrogel with enhanced bacteria contact and bactericidal efficiency for the treatment of various skin infections","authors":"Yongchang Tian , Rong Zhang , Xingjun Zhao , Ian W. Hamley , Chunsheng Xiao , Li Chen","doi":"10.1016/j.biomaterials.2025.123968","DOIUrl":"10.1016/j.biomaterials.2025.123968","url":null,"abstract":"<div><div>Antimicrobial hydrogels that can effectively eliminate microorganisms to accelerate wound healing have demostrated great potential in managing wound infections. However, conventional hydrogel dressings have limited contact with bacteria due to their permemnent cross-linked structure, thereby reducing their bactericidal efficiency. To address this issue, we designed and prepared a neutrophil extracellular traps (NETs) biomimetic antibacterial hydrogel (PETP gel) with enhanced bacteria contact and bactericidal efficiency through Schiff base crosslinking of antibacterial polymer PETP-NH<sub>2</sub> and phenylboronic acid functionalized oxidized hyaluronic acid (OHA-PBA). The obtained PETP gel exhibited a NETs-mimicking dynamic filamentous network structure, which, in combination with the interaction between phenylboronic acid in OHA-PBA and lipopolysaccharides in bacterial surface, ultimately led to enhanced bacteria contact and bactericidal efficiency. <em>In vivo</em> experiments showed that PETP gel could accelerate healing in treatment of purulent subcutaneous infection, full-thickness wound infection, and deep second-degree burn infection, showing promising use as an antibacterial care dressing.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 123968"},"PeriodicalIF":12.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975838","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 : 2026-07-01Epub Date: 2026-01-19DOI: 10.1016/j.biomaterials.2026.124014
Jiahong Ai , Yurong Zhang , Xingwei Li , Fangjun Huo , Caixia Yin
We developed an oral-to-urinalysis theranostic approach for inflammatory bowel disease (IBD) that aims to improve procedural practicality and safety by enabling diagnosis and treatment monitoring without invasive sampling. The strategy exploits disease-associated changes in intestinal chemistry that alter absorption, using the hydrophobicity shift between a fluorescent prodrug (MB-ASA) and its activated product methylene blue (MB). MB-ASA was synthesized by conjugating MB to 5-aminosalicylic acid (5-ASA), a first-line IBD therapy, via a ROS-responsive urea linkage. Owing to its high hydrophobicity, MB-ASA forms aggregates (hydrodynamic diameter ∼531 nm) that limit uptake by intestinal epithelial cells after oral administration in mice. In the inflamed IBD lumen, elevated reactive oxygen species cleave the urea bond, releasing hydrophilic MB and active 5-ASA. The liberated MB is then more readily absorbed and excreted, enabling IBD detection by monitoring fluorescence in the bladder and in excreted urine. Therapeutic activity was supported by histopathological comparisons before and after oral administration of MB-ASA, consistent with local activation and 5-ASA release. This work introduces a fluorescent prodrug platform that couples oral administration with urine-based fluorescence readouts to support theranostic assessment of IBD.
{"title":"An oral-to-urinalysis fluorescent prodrug platform for IBD theranostics","authors":"Jiahong Ai , Yurong Zhang , Xingwei Li , Fangjun Huo , Caixia Yin","doi":"10.1016/j.biomaterials.2026.124014","DOIUrl":"10.1016/j.biomaterials.2026.124014","url":null,"abstract":"<div><div>We developed an oral-to-urinalysis theranostic approach for inflammatory bowel disease (IBD) that aims to improve procedural practicality and safety by enabling diagnosis and treatment monitoring without invasive sampling. The strategy exploits disease-associated changes in intestinal chemistry that alter absorption, using the hydrophobicity shift between a fluorescent prodrug (<strong>MB-ASA</strong>) and its activated product methylene blue (MB). <strong>MB-ASA</strong> was synthesized by conjugating MB to 5-aminosalicylic acid (5-ASA), a first-line IBD therapy, <em>via</em> a ROS-responsive urea linkage. Owing to its high hydrophobicity, <strong>MB-ASA</strong> forms aggregates (hydrodynamic diameter ∼531 nm) that limit uptake by intestinal epithelial cells after oral administration in mice. In the inflamed IBD lumen, elevated reactive oxygen species cleave the urea bond, releasing hydrophilic MB and active 5-ASA. The liberated MB is then more readily absorbed and excreted, enabling IBD detection by monitoring fluorescence in the bladder and in excreted urine. Therapeutic activity was supported by histopathological comparisons before and after oral administration of <strong>MB-ASA</strong>, consistent with local activation and 5-ASA release. This work introduces a fluorescent prodrug platform that couples oral administration with urine-based fluorescence readouts to support theranostic assessment of IBD.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124014"},"PeriodicalIF":12.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-07-01Epub Date: 2026-01-13DOI: 10.1016/j.biomaterials.2026.124002
Seungyong Shin , Ga-Hyun Bae , Joo Dong Park , Eun-Young Koh , Seunghyo Ko , Jieun Han , Chun Gwon Park , Dong-Hyun Kim , Kun Na , Wooram Park
Radiotherapy (RT) is a cornerstone of cancer treatment, but its efficacy is often compromised by robust antioxidant defense mechanisms that counteract radiation-induced oxidative stress. In this study, we developed a novel dual-action nanoplatform, termed radio-activatable lipid nanoparticles (RaLNPs), designed to enhance radiosensitivity by amplifying radiation-induced ferroptosis. RaLNPs incorporate both siRNA targeting glutathione peroxidase 4 (siGPX4), a key ferroptosis defense antioxidant enzyme, and 7-dehydrocholesterol (7-DHC), a radiation-reactive lipid. Notably, the structural lipid cholesterol was completely replaced with 7-DHC, thereby designing the carrier itself to possess a therapeutic function activated by irradiation. The engineered RaLNPs exerted a dual-action mechanism by suppressing GPX4 expression to disable the ferroptosis defense system and, upon irradiation, amplifying 7-DHC–mediated radical chain reactions. Importantly, RaLNPs did not induce oxidative stress or ferroptosis in the absence of radiation, whereas therapeutic irradiation selectively triggered potent and iron-dependent ferroptosis. Beyond direct tumor cell killing, this ferroptotic process also elicited the key hallmarks of immunogenic cell death (ICD), thereby promoting dendritic cell maturation. In a syngeneic 4T1 breast cancer mouse model, the combination of RaLNPs and a single dose of radiation exhibited superior suppression of primary tumor growth and was accompanied by a reduction in metastatic lesions, without systemic toxicity. Analysis of tumor tissues revealed that this therapeutic efficacy was driven by a coordinated immune response, linking T-cell priming in tumor-draining lymph nodes to the sustained intratumoral infiltration of functional cytotoxic T lymphocytes. In conclusion, the RaLNPs developed in this study act as innovative radio-activatable radiosensitizers that simultaneously induce tumor cell death and antitumor immunity specifically in response to irradiation. This work highlights a transformative strategy in which a conventional lipid nanoparticle carrier is evolved into an active therapeutic to overcome the limitations of radiotherapy.
{"title":"Transforming lipid nanoparticles into radio-activatable therapeutics through synergistic ferroptosis for enhanced cancer radiotherapy","authors":"Seungyong Shin , Ga-Hyun Bae , Joo Dong Park , Eun-Young Koh , Seunghyo Ko , Jieun Han , Chun Gwon Park , Dong-Hyun Kim , Kun Na , Wooram Park","doi":"10.1016/j.biomaterials.2026.124002","DOIUrl":"10.1016/j.biomaterials.2026.124002","url":null,"abstract":"<div><div>Radiotherapy (RT) is a cornerstone of cancer treatment, but its efficacy is often compromised by robust antioxidant defense mechanisms that counteract radiation-induced oxidative stress. In this study, we developed a novel dual-action nanoplatform, termed radio-activatable lipid nanoparticles (RaLNPs), designed to enhance radiosensitivity by amplifying radiation-induced ferroptosis. RaLNPs incorporate both siRNA targeting glutathione peroxidase 4 (siGPX4), a key ferroptosis defense antioxidant enzyme, and 7-dehydrocholesterol (7-DHC), a radiation-reactive lipid. Notably, the structural lipid cholesterol was completely replaced with 7-DHC, thereby designing the carrier itself to possess a therapeutic function activated by irradiation. The engineered RaLNPs exerted a dual-action mechanism by suppressing GPX4 expression to disable the ferroptosis defense system and, upon irradiation, amplifying 7-DHC–mediated radical chain reactions. Importantly, RaLNPs did not induce oxidative stress or ferroptosis in the absence of radiation, whereas therapeutic irradiation selectively triggered potent and iron-dependent ferroptosis. Beyond direct tumor cell killing, this ferroptotic process also elicited the key hallmarks of immunogenic cell death (ICD), thereby promoting dendritic cell maturation. In a syngeneic 4T1 breast cancer mouse model, the combination of RaLNPs and a single dose of radiation exhibited superior suppression of primary tumor growth and was accompanied by a reduction in metastatic lesions, without systemic toxicity. Analysis of tumor tissues revealed that this therapeutic efficacy was driven by a coordinated immune response, linking T-cell priming in tumor-draining lymph nodes to the sustained intratumoral infiltration of functional cytotoxic T lymphocytes. In conclusion, the RaLNPs developed in this study act as innovative radio-activatable radiosensitizers that simultaneously induce tumor cell death and antitumor immunity specifically in response to irradiation. This work highlights a transformative strategy in which a conventional lipid nanoparticle carrier is evolved into an active therapeutic to overcome the limitations of radiotherapy.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124002"},"PeriodicalIF":12.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024835","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 : 2026-07-01Epub Date: 2026-01-16DOI: 10.1016/j.biomaterials.2026.124004
Kangling Xie , Yuan Lin , Chuyan Yang , Mingchun Zhao , Xiangying Deng , Wei Du , Nan Jia , Manyuan Wu , Cui Li , Yangjie Li , Jiahao Li , Yujiao Zong , Fan Hu , Ying Cai
Effective treatment of diabetic osteoporotic fractures (DOF) requires biomaterials capable of promoting vascularized bone regeneration. A biodegradable porous zinc (Zn) scaffold incorporating sustained-release Notoginsenoside R1 (NGR1), referred to as Zn-NGR1, was developed using powder metallurgy and impregnation techniques. Comprehensive characterization by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and high-performance liquid chromatography (HPLC) confirmed the scaffold's morphology, composition, and controlled NGR1 release. In a streptozotocin (STZ)-induced diabetic and ovariectomized (OVX) rat model with femoral fractures, Zn-NGR1 implantation markedly accelerated fracture healing, enhanced angiogenesis as demonstrated by hematoxylin and eosin (H&E) staining, Masson's trichrome staining, and immunohistochemistry/immunofluorescence (IHC/IF) analysis for cluster of differentiation 31 (CD31) and vascular endothelial growth factor (VEGF), and improved mechanical strength in three-point bending tests. Bone volume fraction (BV/TV) increased by 20 % compared with controls. Transcriptomic profiling (RNA sequencing, RNA-seq) combined with network pharmacology and machine learning analysis identified the stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling axis as the principal pathway activated by NGR1. In vitro, Zn-NGR1 significantly enhanced bone marrow mesenchymal stem cell (BMSC) and human umbilical vein endothelial cell (HUVEC) proliferation and migration, promoted osteogenic differentiation, and stimulated angiogenesis through SDF-1/CXCR4 upregulation, confirmed by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. In vivo validation demonstrated that Zn-NGR1 facilitates diabetic fracture healing by activating the SDF-1/CXCR4 axis, thereby promoting osteogenesis and angiogenesis. These findings indicate that Zn-NGR1 scaffolds represent a promising biomaterial strategy for improving DOF repair through targeted modulation of the SDF-1/CXCR4 axis.
{"title":"Activating the SDF-1/CXCR4 axis: Notoginsenoside R1-Functionalized zinc scaffolds accelerate fracture healing and angiogenesis in diabetic osteoporosis","authors":"Kangling Xie , Yuan Lin , Chuyan Yang , Mingchun Zhao , Xiangying Deng , Wei Du , Nan Jia , Manyuan Wu , Cui Li , Yangjie Li , Jiahao Li , Yujiao Zong , Fan Hu , Ying Cai","doi":"10.1016/j.biomaterials.2026.124004","DOIUrl":"10.1016/j.biomaterials.2026.124004","url":null,"abstract":"<div><div>Effective treatment of diabetic osteoporotic fractures (DOF) requires biomaterials capable of promoting vascularized bone regeneration. A biodegradable porous zinc (Zn) scaffold incorporating sustained-release Notoginsenoside R1 (NGR1), referred to as Zn-NGR1, was developed using powder metallurgy and impregnation techniques. Comprehensive characterization by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and high-performance liquid chromatography (HPLC) confirmed the scaffold's morphology, composition, and controlled NGR1 release. In a streptozotocin (STZ)-induced diabetic and ovariectomized (OVX) rat model with femoral fractures, Zn-NGR1 implantation markedly accelerated fracture healing, enhanced angiogenesis as demonstrated by hematoxylin and eosin (H&E) staining, Masson's trichrome staining, and immunohistochemistry/immunofluorescence (IHC/IF) analysis for cluster of differentiation 31 (CD31) and vascular endothelial growth factor (VEGF), and improved mechanical strength in three-point bending tests. Bone volume fraction (BV/TV) increased by 20 % compared with controls. Transcriptomic profiling (RNA sequencing, RNA-seq) combined with network pharmacology and machine learning analysis identified the stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling axis as the principal pathway activated by NGR1. <em>In vitro</em>, Zn-NGR1 significantly enhanced bone marrow mesenchymal stem cell (BMSC) and human umbilical vein endothelial cell (HUVEC) proliferation and migration, promoted osteogenic differentiation, and stimulated angiogenesis through SDF-1/CXCR4 upregulation, confirmed by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. <em>In vivo</em> validation demonstrated that Zn-NGR1 facilitates diabetic fracture healing by activating the SDF-1/CXCR4 axis, thereby promoting osteogenesis and angiogenesis. These findings indicate that Zn-NGR1 scaffolds represent a promising biomaterial strategy for improving DOF repair through targeted modulation of the SDF-1/CXCR4 axis.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124004"},"PeriodicalIF":12.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024840","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 : 2026-06-01Epub Date: 2025-12-15DOI: 10.1016/j.biomaterials.2025.123920
Miao Huang , Yinong Chen , Chenyu Liang , Om Prakash Narayan , Chase Stallings , Mu Yu , Conner Traugot , Lu Li , Keming Li , Quang Vo , Heyang Wang , Yu-Ting Chou , Lauren Cech , Daniel Parra , Laura Garzon , Dylan Parsons , Emma Diaz , Cunyu Zhang , Cole Mackey , Hayley Sussman , Xin Tang
Drug resistance is a leading cause of cancer treatment failure and tumor recurrence. Identifying new methods that eliminate life-threatening drug-resistant cancer cells (DRCs) can enhance tumor cell eradication and improve patient outcomes. Here we report that human non-small cell lung cancer (NSCLC) DRCs show previously unrecognized increased sensitivity to mechanical stimuli compared to drug-susceptible lung cancer cells (DSCs) in vitro. Exploiting this heightened mechanical sensitivity, the combination of physiologically soft culture microenvironment with targeted therapies reduces the survival of DRCs through regulating yes-associated-protein (YAP) translocation between nucleus and cytoplasm. Our clinical studies confirm that DRCs possess heightened YAP nuclear localization in both NSCLC patient-derived organoid models and patient tissues, indicating high potential of eradicating DRCs by mechanical stimuli in vivo. Further, our mechanistic analyses, including quantitative imaging, transcriptomic profiling, and pharmacological evaluations reveal that the alterations in nuclear force sensing, rather than actomyosin contractility or Hippo-YAP pathway activation in DRCs, primarily drive the heightened YAP mechanosensitivity. This work highlights the crucial difference in mechanosensitivity between DRCs and DSCs, and points to mechanobiological targeting of these cells as a novel strategy to overcome drug resistance and enhance cancer therapy.
{"title":"Drug resistant cancer cells show increased nuclear mechanotransduction and mechanically targetable YAP-regulated vulnerability","authors":"Miao Huang , Yinong Chen , Chenyu Liang , Om Prakash Narayan , Chase Stallings , Mu Yu , Conner Traugot , Lu Li , Keming Li , Quang Vo , Heyang Wang , Yu-Ting Chou , Lauren Cech , Daniel Parra , Laura Garzon , Dylan Parsons , Emma Diaz , Cunyu Zhang , Cole Mackey , Hayley Sussman , Xin Tang","doi":"10.1016/j.biomaterials.2025.123920","DOIUrl":"10.1016/j.biomaterials.2025.123920","url":null,"abstract":"<div><div>Drug resistance is a leading cause of cancer treatment failure and tumor recurrence. Identifying new methods that eliminate life-threatening drug-resistant cancer cells (DRCs) can enhance tumor cell eradication and improve patient outcomes. Here we report that human non-small cell lung cancer (NSCLC) DRCs show previously unrecognized increased sensitivity to mechanical stimuli compared to drug-susceptible lung cancer cells (DSCs) <em>in vitro</em>. Exploiting this heightened mechanical sensitivity, the combination of physiologically soft culture microenvironment with targeted therapies reduces the survival of DRCs through regulating yes-associated-protein (YAP) translocation between nucleus and cytoplasm. Our clinical studies confirm that DRCs possess heightened YAP nuclear localization in both NSCLC patient-derived organoid models and patient tissues, indicating high potential of eradicating DRCs by mechanical stimuli <em>in vivo</em>. Further, our mechanistic analyses, including quantitative imaging, transcriptomic profiling, and pharmacological evaluations reveal that the alterations in nuclear force sensing, rather than actomyosin contractility or Hippo-YAP pathway activation in DRCs, primarily drive the heightened YAP mechanosensitivity. This work highlights the crucial difference in mechanosensitivity between DRCs and DSCs, and points to mechanobiological targeting of these cells as a novel strategy to overcome drug resistance and enhance cancer therapy.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123920"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145825570","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 : 2026-06-01Epub Date: 2026-01-10DOI: 10.1016/j.biomaterials.2026.123995
Yiming Liu , Jiheng Shan , Chengzhi Zhang , Junheng Zhang , Yilin Liu , Changlong Li , Peiyao Sun , Dechao Jiao , Haidong Zhu , Zhen Li , Xinwei Han , Yanan Zhao
Postoperative liver cancer relapse remains a formidable clinical challenge. Photothermal therapy (PTT) holds promise by eliminating residual malignancies and activating antitumor immunity; notably, tumor cells persistently reconstitute proteostasis and survive by integrated stress response (ISR)-mediated heat shock protein 90 (HSP90) activation to constrain PTT efficacy. To address this limitation, we engineered a self-reinforced photothermal-immunomodulation strategy based on electrospun nanofiber scaffolds co-loaded with black phosphorus nanosheets (BPNSs) and the HSP90 inhibitor 17-DMAG. These nanofiber scaffolds exhibited robust hydrophobicity, efficient photothermal conversion, and near-infrared (NIR) responsive controlled drug release. Under NIR irradiation, the nanofiber scaffolds leveraged BPNSs to generate stable PTT while liberating 17-DMAG to amplify proteotoxicity, forcibly redirecting the ISR from pro-survival adaptation toward robust apoptosis and immunogenic cell death (ICD). Consequently, prominently exposed damage-associated molecular patterns potentiated tumor immunogenicity and remodeled immune microenvironment by dendritic cells maturation, cytotoxic T lymphocytes (CTLs) priming, and immunosuppressive populations reprogramming. Crucially, subsequent synergy with anti-PD-L1 reinvigorated CTLs and established durable immune memory. Systematic validation confirmed this localized strategy uniquely integrates precision photothermal energy conversion with potent ISR-ICD cascade, effectively synergizing with anti-PD-L1 to suppress postoperative liver cancer relapse and metastasis, thereby holding substantial translational potential for clinical oncology.
{"title":"Self-reinforced photothermal-immunomodulation potentiating ISR-ICD cascade against postoperative relapse","authors":"Yiming Liu , Jiheng Shan , Chengzhi Zhang , Junheng Zhang , Yilin Liu , Changlong Li , Peiyao Sun , Dechao Jiao , Haidong Zhu , Zhen Li , Xinwei Han , Yanan Zhao","doi":"10.1016/j.biomaterials.2026.123995","DOIUrl":"10.1016/j.biomaterials.2026.123995","url":null,"abstract":"<div><div>Postoperative liver cancer relapse remains a formidable clinical challenge. Photothermal therapy (PTT) holds promise by eliminating residual malignancies and activating antitumor immunity; notably, tumor cells persistently reconstitute proteostasis and survive by integrated stress response (ISR)-mediated heat shock protein 90 (HSP90) activation to constrain PTT efficacy. To address this limitation, we engineered a self-reinforced photothermal-immunomodulation strategy based on electrospun nanofiber scaffolds co-loaded with black phosphorus nanosheets (BPNSs) and the HSP90 inhibitor 17-DMAG. These nanofiber scaffolds exhibited robust hydrophobicity, efficient photothermal conversion, and near-infrared (NIR) responsive controlled drug release. Under NIR irradiation, the nanofiber scaffolds leveraged BPNSs to generate stable PTT while liberating 17-DMAG to amplify proteotoxicity, forcibly redirecting the ISR from pro-survival adaptation toward robust apoptosis and immunogenic cell death (ICD). Consequently, prominently exposed damage-associated molecular patterns potentiated tumor immunogenicity and remodeled immune microenvironment by dendritic cells maturation, cytotoxic T lymphocytes (CTLs) priming, and immunosuppressive populations reprogramming. Crucially, subsequent synergy with anti-PD-L1 reinvigorated CTLs and established durable immune memory. Systematic validation confirmed this localized strategy uniquely integrates precision photothermal energy conversion with potent ISR-ICD cascade, effectively synergizing with anti-PD-L1 to suppress postoperative liver cancer relapse and metastasis, thereby holding substantial translational potential for clinical oncology.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123995"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973456","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 : 2026-06-01Epub Date: 2025-12-17DOI: 10.1016/j.biomaterials.2025.123911
Qingge Ma , Chenghao Song , Zhengmin Zhang , Feifei Li , Peng Yu , Ling Ye
The osteogenic differentiation of mesenchymal stem cells (MSCs) requires dynamic remodeling of the extracellular matrix (ECM) microenvironment. Biomimetic mineralization (BM) can recapitulate key features of the native bone microenvironment and thereby promote MSC osteogenesis. However, the development of artificial scaffolds capable of providing dynamically evolving mineralized niches for MSCs remains challenging, and the underlying osteogenic mechanisms are still poorly understood. In this study, a hierarchical graphene-doped polymethyl methacrylate (PMMA) scaffold was fabricated via vapor-induced phase separation. An organic-inorganic framework with continuous self-mineralization capability—composed of ovalbumin (OVA), tannins (TA), Ca2+, and PO43-—was engineered on the graphene surface through a simple two-step immersion process. This bone tissue mimetic architecture, combined with sustained in situ mineralization, establishes an optimal dynamic niche that supports MSC adhesion and drives robust osteogenic differentiation. Furthermore, the self-mineralized calcium nodules synergize with MSC-mediated calcium deposition during osteogenesis, leading to accelerated scaffold remodeling and a significantly shortened bone repair timeline. Collectively, the hierarchical scaffold featuring a self-mineralizing MSC niche exhibits strong potential for the regeneration of critical-sized bone defects.
{"title":"Artificial self-mineralized MSCs’ niche mimics dynamic variations of ECM modulus during osteogenesis for rapid bone regeneration","authors":"Qingge Ma , Chenghao Song , Zhengmin Zhang , Feifei Li , Peng Yu , Ling Ye","doi":"10.1016/j.biomaterials.2025.123911","DOIUrl":"10.1016/j.biomaterials.2025.123911","url":null,"abstract":"<div><div>The osteogenic differentiation of mesenchymal stem cells (MSCs) requires dynamic remodeling of the extracellular matrix (ECM) microenvironment. Biomimetic mineralization (BM) can recapitulate key features of the native bone microenvironment and thereby promote MSC osteogenesis. However, the development of artificial scaffolds capable of providing dynamically evolving mineralized niches for MSCs remains challenging, and the underlying osteogenic mechanisms are still poorly understood. In this study, a hierarchical graphene-doped polymethyl methacrylate (PMMA) scaffold was fabricated via vapor-induced phase separation. An organic-inorganic framework with continuous self-mineralization capability—composed of ovalbumin (OVA), tannins (TA), Ca<sup>2+</sup>, and PO<sub>4</sub><sup>3-</sup>—was engineered on the graphene surface through a simple two-step immersion process. This bone tissue mimetic architecture, combined with sustained <em>in situ</em> mineralization, establishes an optimal dynamic niche that supports MSC adhesion and drives robust osteogenic differentiation. Furthermore, the self-mineralized calcium nodules synergize with MSC-mediated calcium deposition during osteogenesis, leading to accelerated scaffold remodeling and a significantly shortened bone repair timeline. Collectively, the hierarchical scaffold featuring a self-mineralizing MSC niche exhibits strong potential for the regeneration of critical-sized bone defects.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123911"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799418","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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