Pub Date : 2026-01-18DOI: 10.1016/j.biomaterials.2026.124009
Shengnan Fu , Zhixin Li , Zhe Yin , Xi Zhang , Xiaolin Song , Lingfei Hu , Dongsheng Zhou , Xin Su , Chenxi Dai
Pneumonic plague, caused by Yersinia pestis, remains a deadly threat due to its high mortality and rapid progression. In our previous study, Yersinia pestis antigens formulated with CpG oligodeoxynucleotides show great potential against pneumonic plague, but these agonists display low TLR9 affinity, poor stability, limited cellular uptake, and weak induction of tissue-resident memory immunity. Here, we introduce AdjCRU, a cruciform DNA nano-adjuvant built on a four-way junction with each arm presenting looped CpG motifs (LoDNA) for TLR9 engagement. Guided by computational design and molecular dynamics simulations, the four-way junction is chosen over other nanostructures for superior TLR9 binding. AdjCRU is nuclease-resistant, prepared by one-step annealing of four single-stranded oligonucleotides. When administered via aerosolized intratracheal inoculation alongside Yersinia pestis recombinant antigen rV10, AdjCRU is effectively internalized into lysosomes of antigen-presenting cell (APC), inducing markedly enhanced APC maturation, germinal center reaction, systemic and mucosal antibody titers, and T/B cell activation. Notably, rV10+AdjCRU drives robust lung-resident memory T/B cell immunity, and significantly improves survival by 40 % over free LoDNA in a lethal pneumonic plague mouse model. By integrating programmability, biocompatibility, and enhanced TLR9 stimulation into a single, modular platform, AdjCRU offers a versatile strategy for next-generation mucosal adjuvants against respiratory pathogens.
{"title":"Inhalable DNA nano-adjuvant elicits robust lung-resident memory immunity against pneumonic plague","authors":"Shengnan Fu , Zhixin Li , Zhe Yin , Xi Zhang , Xiaolin Song , Lingfei Hu , Dongsheng Zhou , Xin Su , Chenxi Dai","doi":"10.1016/j.biomaterials.2026.124009","DOIUrl":"10.1016/j.biomaterials.2026.124009","url":null,"abstract":"<div><div>Pneumonic plague, caused by <em>Yersinia pestis</em>, remains a deadly threat due to its high mortality and rapid progression. In our previous study, <em>Yersinia pestis</em> antigens formulated with CpG oligodeoxynucleotides show great potential against pneumonic plague, but these agonists display low TLR9 affinity, poor stability, limited cellular uptake, and weak induction of tissue-resident memory immunity. Here, we introduce AdjCRU, a cruciform DNA nano-adjuvant built on a four-way junction with each arm presenting looped CpG motifs (LoDNA) for TLR9 engagement. Guided by computational design and molecular dynamics simulations, the four-way junction is chosen over other nanostructures for superior TLR9 binding. AdjCRU is nuclease-resistant, prepared by one-step annealing of four single-stranded oligonucleotides. When administered via aerosolized intratracheal inoculation alongside <em>Yersinia pestis</em> recombinant antigen rV10, AdjCRU is effectively internalized into lysosomes of antigen-presenting cell (APC), inducing markedly enhanced APC maturation, germinal center reaction, systemic and mucosal antibody titers, and T/B cell activation. Notably, rV10+AdjCRU drives robust lung-resident memory T/B cell immunity, and significantly improves survival by 40 % over free LoDNA in a lethal pneumonic plague mouse model. By integrating programmability, biocompatibility, and enhanced TLR9 stimulation into a single, modular platform, AdjCRU offers a versatile strategy for next-generation mucosal adjuvants against respiratory pathogens.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124009"},"PeriodicalIF":12.9,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024837","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 : 2026-01-17DOI: 10.1016/j.biomaterials.2026.124007
Zhiqing Lin , Haoyue Deng , Guang Yang , Keke Huang
Retinal ischemia-reperfusion injury (RIRI) is a central pathological mechanism in vision-impairing disorders such as glaucoma and retinal vascular occlusion. Current treatment modalities are significantly constrained by their inability to simultaneously address the multifaceted injury cascades driven by lethal oxidative stress, ferroptosis, and neuroinflammation, which considerably limits their clinical efficacy. To overcome these challenges, we designed a nanocomposite, termed P-PPy, by integrating polydopamine with conducting polypyrrole. Within this construct, surface-modified polydopamine (PDA) acts as a biosponge that effectively chelates excess iron ions. A single intravitreal injection of P-PPy elicited broad therapeutic responses, including efficient reactive oxygen species (ROS) scavenging, inhibition of ferroptosis in retinal ganglion cells accompanied by restoration of mitochondrial functionality, and induction of M2 microglial polarization leading to attenuated neuroinflammation. Together, these mechanisms synergistically restored the electrophysiological microenvironment of the retina, markedly preserving both its structural integrity and functional performance. The P-PPy nanocomposite also demonstrated an excellent biosafety profile, exhibiting no detectable toxicity in both cellular assays and following intravitreal administration in animal models. In summary, this readily synthesizable, multifunctional conductive nanoplatform provides strong neuroprotective effects in vivo, offering a promising therapeutic avenue based on conductive nanomaterials for the treatment of neurodegenerative retinal diseases.
{"title":"Biosponge-armored polydopamine-modified conducting polypyrrole restores redox-iron homeostasis for enhanced neuroprotection in retinal ischemia-reperfusion injury","authors":"Zhiqing Lin , Haoyue Deng , Guang Yang , Keke Huang","doi":"10.1016/j.biomaterials.2026.124007","DOIUrl":"10.1016/j.biomaterials.2026.124007","url":null,"abstract":"<div><div>Retinal ischemia-reperfusion injury (RIRI) is a central pathological mechanism in vision-impairing disorders such as glaucoma and retinal vascular occlusion. Current treatment modalities are significantly constrained by their inability to simultaneously address the multifaceted injury cascades driven by lethal oxidative stress, ferroptosis, and neuroinflammation, which considerably limits their clinical efficacy. To overcome these challenges, we designed a nanocomposite, termed P-PPy, by integrating polydopamine with conducting polypyrrole. Within this construct, surface-modified polydopamine (PDA) acts as a biosponge that effectively chelates excess iron ions. A single intravitreal injection of P-PPy elicited broad therapeutic responses, including efficient reactive oxygen species (ROS) scavenging, inhibition of ferroptosis in retinal ganglion cells accompanied by restoration of mitochondrial functionality, and induction of M2 microglial polarization leading to attenuated neuroinflammation. Together, these mechanisms synergistically restored the electrophysiological microenvironment of the retina, markedly preserving both its structural integrity and functional performance. The P-PPy nanocomposite also demonstrated an excellent biosafety profile, exhibiting no detectable toxicity in both cellular assays and following intravitreal administration in animal models. In summary, this readily synthesizable, multifunctional conductive nanoplatform provides strong neuroprotective effects in vivo, offering a promising therapeutic avenue based on conductive nanomaterials for the treatment of neurodegenerative retinal diseases.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124007"},"PeriodicalIF":12.9,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024836","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 : 2026-01-17DOI: 10.1016/j.biomaterials.2025.123971
Kuikun Yang , Yijing Liu , Yin Wang , Qilong Ren , Hongyu Guo , John B. Matson , Xiaoyuan Chen , Zhihong Nie
{"title":"Corrigendum to ‘Enzyme-induced in vivo assembly of gold nanoparticles for imaging-guided synergistic chemo-photothermal therapy of tumor’ [Biomaterials 223 (2019) 119460]","authors":"Kuikun Yang , Yijing Liu , Yin Wang , Qilong Ren , Hongyu Guo , John B. Matson , Xiaoyuan Chen , Zhihong Nie","doi":"10.1016/j.biomaterials.2025.123971","DOIUrl":"10.1016/j.biomaterials.2025.123971","url":null,"abstract":"","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123971"},"PeriodicalIF":12.9,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996801","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 : 2026-01-17DOI: 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":"2026-01-17","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 : 2026-01-16DOI: 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":"2026-01-16","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 : 2026-01-14DOI: 10.1016/j.biomaterials.2026.124005
Liang Song , Yongyuan Kang , Pai Peng , Qiaoxuan Wang , Liyin Shen , Jinyue Zhang , Yang Zhu , Changyou Gao
Myocardial infarction (MI) often leads to excessive lactate accumulation, which drives endothelial-to-mesenchymal transition (EndoMT) and subsequent myocardial fibrosis. Lactate oxidase (LOx) has been identified as a potential therapeutic enzyme capable of degrading excess lactate. However, the hypoxic environment characteristic of MI diminishes the catalytic efficiency of LOx. In this study, platinum (Pt) nanozymes with catalase-like (CAT-like) activity were introduced, which catalyzed the decomposition of hydrogen peroxide (H2O2) to generate oxygen (O2), thereby enhancing LOx activity. A strategy involving microgel-anchored LOx-loaded Pt nanozymes (PPtL@MGs) was proposed by loading LOx-loaded Pt nanozymes to microgels, enabling targeted delivery and prolonged retention within the infarcted myocardium. The PPtL@MGs exhibited robust CAT-like activity and effectively enhanced LOx-mediated lactate clearance in vitro, thereby alleviating hypoxia/H2O2-induced EndoMT in HUVECs. Consequently, it promoted vascular endothelial cadherin (VE-cadherin) expression, suppressed fibroblast-specific protein 1 (FSP1), reduced myocardial fibrosis, and significantly improved cardiac function in vivo. These results demonstrate the potential of this microgel-anchored nanozyme system, which enables cascade-enhanced lactate modulation through O2 generation and effective lactate clearance, thereby alleviating the MI-induced fibrosis and dysfunction.
{"title":"Cascade-enhanced Pt nanozyme platform anchored on microgels for effective lactate depletion and EndoMT attenuation post-myocardial infarction","authors":"Liang Song , Yongyuan Kang , Pai Peng , Qiaoxuan Wang , Liyin Shen , Jinyue Zhang , Yang Zhu , Changyou Gao","doi":"10.1016/j.biomaterials.2026.124005","DOIUrl":"10.1016/j.biomaterials.2026.124005","url":null,"abstract":"<div><div>Myocardial infarction (MI) often leads to excessive lactate accumulation, which drives endothelial-to-mesenchymal transition (EndoMT) and subsequent myocardial fibrosis. Lactate oxidase (LOx) has been identified as a potential therapeutic enzyme capable of degrading excess lactate. However, the hypoxic environment characteristic of MI diminishes the catalytic efficiency of LOx. In this study, platinum (Pt) nanozymes with catalase-like (CAT-like) activity were introduced, which catalyzed the decomposition of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) to generate oxygen (O<sub>2</sub>), thereby enhancing LOx activity. A strategy involving microgel-anchored LOx-loaded Pt nanozymes (PPtL@MGs) was proposed by loading LOx-loaded Pt nanozymes to microgels, enabling targeted delivery and prolonged retention within the infarcted myocardium. The PPtL@MGs exhibited robust CAT-like activity and effectively enhanced LOx-mediated lactate clearance <em>in vitro</em>, thereby alleviating hypoxia/H<sub>2</sub>O<sub>2</sub>-induced EndoMT in HUVECs. Consequently, it promoted vascular endothelial cadherin (VE-cadherin) expression, suppressed fibroblast-specific protein 1 (FSP1), reduced myocardial fibrosis, and significantly improved cardiac function <em>in vivo</em>. These results demonstrate the potential of this microgel-anchored nanozyme system, which enables cascade-enhanced lactate modulation through O<sub>2</sub> generation and effective lactate clearance, thereby alleviating the MI-induced fibrosis and dysfunction.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 124005"},"PeriodicalIF":12.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024833","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 : 2026-01-14DOI: 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":"2026-01-14","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 : 2026-01-13DOI: 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":"2026-01-13","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 : 2026-01-12DOI: 10.1016/j.biomaterials.2026.123994
Jialing Zhou , Jiang Ming , Zhenfeng Yu , Zhihua Wang , Wenlin Li , Ahmed Mohamed El-Toni , Aliyah Almomen , Aibin Liang , Yong Fan , Fan Zhang
Photodynamic therapy (PDT) that induces pyroptosis at the cell membrane has emerged as a promising paradigm for cancer immunotherapy. However, the rapid and precise induction of pyroptosis remains a significant challenge. To address this, we developed a near-infrared orthogonal excitation lanthanide theranostic nanoplatform based on lanthanide doped nanoparticles conjugated with curcumin (CUR) and cyclo(RGD-DPhe-K) peptide (LnNP@CUR-RGD). This platform enables deep-tissue, NIR-II-L imaging-guided PDT that concurrently initiates both pyroptosis and apoptosis. Upon 808 nm excitation, fluorescence at 1530 nm from LnNP@CUR-RGD allows for real-time in vivo tracking and monitoring of its localization to the cell membrane or lysosome. After subsequently switching to 940 nm excitation, the produced 362 nm emission activates CUR to generate singlet oxygen (1O2). This process initiates a dual-death mechanism: cell membrane-involved pyroptosis and lysosome-involved apoptosis, which synergistically potentiate the anti-tumor immune response. Notably, this nanoplatform achieves efficient antitumor therapy within 15 min of systemic administration, a significant acceleration compared to the 6 h required for conventional apoptosis-based PDT. This work demonstrates the considerable potential of NIR-light-triggered, targeted theranostic platforms for precise imaging-guided cancer therapy.
{"title":"Near-infrared orthogonal excitation lanthanide theranostic nanoplatform for NIR-II-L imaging-guided photodynamic therapy via synergistical pyroptosis and apoptosis pathway","authors":"Jialing Zhou , Jiang Ming , Zhenfeng Yu , Zhihua Wang , Wenlin Li , Ahmed Mohamed El-Toni , Aliyah Almomen , Aibin Liang , Yong Fan , Fan Zhang","doi":"10.1016/j.biomaterials.2026.123994","DOIUrl":"10.1016/j.biomaterials.2026.123994","url":null,"abstract":"<div><div>Photodynamic therapy (PDT) that induces pyroptosis at the cell membrane has emerged as a promising paradigm for cancer immunotherapy. However, the rapid and precise induction of pyroptosis remains a significant challenge. To address this, we developed a near-infrared orthogonal excitation lanthanide theranostic nanoplatform based on lanthanide doped nanoparticles conjugated with curcumin (CUR) and cyclo(RGD-DPhe-K) peptide (LnNP@CUR-RGD). This platform enables deep-tissue, NIR-II-L imaging-guided PDT that concurrently initiates both pyroptosis and apoptosis. Upon 808 nm excitation, fluorescence at 1530 nm from LnNP@CUR-RGD allows for real-time in vivo tracking and monitoring of its localization to the cell membrane or lysosome. After subsequently switching to 940 nm excitation, the produced 362 nm emission activates CUR to generate singlet oxygen (<sup>1</sup>O<sub>2</sub>). This process initiates a dual-death mechanism: cell membrane-involved pyroptosis and lysosome-involved apoptosis, which synergistically potentiate the anti-tumor immune response. Notably, this nanoplatform achieves efficient antitumor therapy within 15 min of systemic administration, a significant acceleration compared to the 6 h required for conventional apoptosis-based PDT. This work demonstrates the considerable potential of NIR-light-triggered, targeted theranostic platforms for precise imaging-guided cancer therapy.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 123994"},"PeriodicalIF":12.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008015","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 : 2026-01-12DOI: 10.1016/j.biomaterials.2026.123989
Xiaoqing Sun , Xingyou Wang , Meihua Zhang , Shuyao Liu , Yue Zhu , Jing He , Yao Wu
With the aging population, treating age-related osteoporosis remains challenging due to the dysfunctional bone marrow microenvironment characterized by chronic inflammation, metabolic dysregulation, and impaired mitochondrial function in senescent cells. While mitochondrial transfer from macrophages to bone marrow mesenchymal stem cells (BMSCs) offers a promising therapeutic avenue, its efficacy is limited in aged niches where donor mitochondria exhibit functional deficits and poor recipient compatibility. We engineered KGM-PEG-SPIONs, functionalized Fe3O4 nanoparticles that enhance donor mitochondrial quality via autophagy activation and Fe–S cluster biogenesis, promote M2 macrophage polarization, and improve compatibility with the oxidative and inflammatory environment of senescent BMSCs. These M2-like mitochondria are transferred through connexin 43 gap junctions, restoring membrane potential, ATP production, calcium homeostasis, and osteogenic differentiation in recipient cells. In aged osteoporotic models, KGM-PEG-SPION-functionalized scaffolds remodel immune niches and promote bone formation. By integrating organelle quality control with environment-adapted mitochondrial transfer, this strategy surpasses approaches focusing solely on transfer quantity or polarization, establishing a programmable nanoplatform for organelle-based regeneration.
{"title":"Iron oxide nanoparticles-driven mitochondrial renewal rejuvenates the aged bone marrow niche","authors":"Xiaoqing Sun , Xingyou Wang , Meihua Zhang , Shuyao Liu , Yue Zhu , Jing He , Yao Wu","doi":"10.1016/j.biomaterials.2026.123989","DOIUrl":"10.1016/j.biomaterials.2026.123989","url":null,"abstract":"<div><div>With the aging population, treating age-related osteoporosis remains challenging due to the dysfunctional bone marrow microenvironment characterized by chronic inflammation, metabolic dysregulation, and impaired mitochondrial function in senescent cells. While mitochondrial transfer from macrophages to bone marrow mesenchymal stem cells (BMSCs) offers a promising therapeutic avenue, its efficacy is limited in aged niches where donor mitochondria exhibit functional deficits and poor recipient compatibility. We engineered KGM-PEG-SPIONs, functionalized Fe<sub>3</sub>O<sub>4</sub> nanoparticles that enhance donor mitochondrial quality via autophagy activation and Fe–S cluster biogenesis, promote M2 macrophage polarization, and improve compatibility with the oxidative and inflammatory environment of senescent BMSCs. These M2-like mitochondria are transferred through connexin 43 gap junctions, restoring membrane potential, ATP production, calcium homeostasis, and osteogenic differentiation in recipient cells. In aged osteoporotic models, KGM-PEG-SPION-functionalized scaffolds remodel immune niches and promote bone formation. By integrating organelle quality control with environment-adapted mitochondrial transfer, this strategy surpasses approaches focusing solely on transfer quantity or polarization, establishing a programmable nanoplatform for organelle-based regeneration.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"330 ","pages":"Article 123989"},"PeriodicalIF":12.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957408","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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