Pub Date : 2024-07-14DOI: 10.1016/j.biomaterials.2024.122702
WeiYi Cheng , WeiYe Ren , Peng Ye , Li He , Dandan Bao , Tianxiang Yue , Jianjun Lai , Yajun Wu , YingHui Wei , Zhibing Wu , Ji-Gang Piao
The blood-brain barrier (BBB) is a complex and highly restrictive barrier that prevents most biomolecules and drugs from entering the brain. However, effective strategies for delivering drugs to the brain are urgently needed for the treatment of glioblastoma. Based on the efficient BBB penetration properties of exosomes derived from brain metastatic breast cancer cells (EB), this work prepared a nanoreactor (denoted as MAG@EB), which was constructed by self-assembly of Mn2+, arsenate and glucose oxidase (GOx) into nanoparticles wrapped with EB. MAG@EB can enhance the efficiency of traversing the BBB, target and accumulate at in situ glioblastoma sites. The GOx-driven glycolysis effectively cuts off the glucose supply while also providing an abundance of H2O2 and lowering pH. Meanwhile, the released Mn2+ mediated Fenton-like reaction converts elevated H2O2 into highly toxic ·OH. Besides, AsV was reduced to AsIII by glutathione, and the tumor suppressor gene P53 was activated by AsIII to kill glioblastoma cells. Glioblastoma succumbed to the redox cascade triggered by MAG@EB, as the results demonstrated in vivo and in vitro, yielding a remarkable therapeutic effect. This work provides a promising therapeutic option mediated by cascaded nanoreactors for the future treatment of glioblastoma.
{"title":"Camouflaging nanoreactor traverse the blood-brain barrier to catalyze redox cascade for synergistic therapy of glioblastoma","authors":"WeiYi Cheng , WeiYe Ren , Peng Ye , Li He , Dandan Bao , Tianxiang Yue , Jianjun Lai , Yajun Wu , YingHui Wei , Zhibing Wu , Ji-Gang Piao","doi":"10.1016/j.biomaterials.2024.122702","DOIUrl":"https://doi.org/10.1016/j.biomaterials.2024.122702","url":null,"abstract":"<div><p>The blood-brain barrier (BBB) is a complex and highly restrictive barrier that prevents most biomolecules and drugs from entering the brain. However, effective strategies for delivering drugs to the brain are urgently needed for the treatment of glioblastoma. Based on the efficient BBB penetration properties of exosomes derived from brain metastatic breast cancer cells (EB), this work prepared a nanoreactor (denoted as MAG@EB), which was constructed by self-assembly of Mn<sup>2+</sup>, arsenate and glucose oxidase (GOx) into nanoparticles wrapped with EB. MAG@EB can enhance the efficiency of traversing the BBB, target and accumulate at in situ glioblastoma sites. The GOx-driven glycolysis effectively cuts off the glucose supply while also providing an abundance of H<sub>2</sub>O<sub>2</sub> and lowering pH. Meanwhile, the released Mn<sup>2+</sup> mediated Fenton-like reaction converts elevated H<sub>2</sub>O<sub>2</sub> into highly toxic ·OH. Besides, AsV was reduced to AsIII by glutathione, and the tumor suppressor gene P53 was activated by AsIII to kill glioblastoma cells. Glioblastoma succumbed to the redox cascade triggered by MAG@EB, as the results demonstrated in vivo and in vitro, yielding a remarkable therapeutic effect. This work provides a promising therapeutic option mediated by cascaded nanoreactors for the future treatment of glioblastoma.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141607119","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 : 2024-07-08DOI: 10.1016/j.biomaterials.2024.122703
Jiake Lin , Yuemin Zhou , Chen Li , Benke Li , Haibin Hao , Fengchao Tian , Huixin Li , Zhenyu Liu , Guangchuan Wang , Xing-Can Shen , Ruikang Tang , Xiaoyu Wang
An obstacle in current tumor immunotherapies lies in the challenge of achieving sustained and tumor-targeting T cell immunity, impeded by the limited antigen processing and cross-presentation of tumor antigens. Here, we propose a hydrogel-based multicellular immune factory within the body that autonomously converts tumor cells into an antitumor vaccine. Within the body, the scaffold, formed by a calcium-containing chitosan hydrogel complex (ChitoCa) entraps tumor cells and attracts immune cells to establish a durable and multicellular microenvironment. Within this context, tumor cells are completely eliminated by antigen-presenting cells (APCs) and processed for cross-antigen presentation. The regulatory mechanism relies on the Mincle receptor, a cell-phagocytosis-inducing C-type lectin receptor specifically activated on ChitoCa-recruited APCs, which serves as a recognition synapse, facilitating a tenfold increase in tumor cell engulfment and subsequent elimination. The ChitoCa-induced tumor cell processing further promotes the cross-presentation of tumor antigens to prime protective CD8+ T cell responses. Therefore, the ChitoCa treatment establishes an immune niche within the tumor microenvironment, resulting in effective tumor regression either used alone or in combination with other immunotherapies. This hydrogel-induced immune factory establishes a functional organ-like multicellular colony for tumor-specific immunotherapy, paving the way for innovative strategies in cancer treatment.
目前肿瘤免疫疗法的一个障碍在于,由于肿瘤抗原的处理和交叉呈递能力有限,实现持续的肿瘤靶向 T 细胞免疫面临挑战。在这里,我们提出了一种基于水凝胶的体内多细胞免疫工厂,它能自主地将肿瘤细胞转化为抗肿瘤疫苗。在人体内,由含钙壳聚糖水凝胶复合物(ChitoCa)形成的支架可诱捕肿瘤细胞并吸引免疫细胞,从而建立一个持久的多细胞微环境。在这种环境下,肿瘤细胞会被抗原递呈细胞(APCs)完全清除,并经过处理后进行交叉抗原递呈。调节机制依赖于 Mincle 受体,这是一种细胞吞噬诱导 C 型凝集素受体,在 ChitoCa 诱导的 APCs 上被特异性激活,可作为识别突触,促进肿瘤细胞吞噬量和随后的消除量增加十倍。ChitoCa 诱导的肿瘤细胞处理进一步促进了肿瘤抗原的交叉呈递,激发了保护性 CD8+ T 细胞反应。因此,ChitoCa疗法在肿瘤微环境中建立了一个免疫龛,无论是单独使用还是与其他免疫疗法结合使用,都能有效消退肿瘤。这种水凝胶诱导的免疫工厂为肿瘤特异性免疫疗法建立了一个类似器官的多细胞功能群,为癌症治疗的创新策略铺平了道路。
{"title":"Hydrogel activation of Mincle receptors for tumor cell processing: A novel approach in cancer immunotherapy","authors":"Jiake Lin , Yuemin Zhou , Chen Li , Benke Li , Haibin Hao , Fengchao Tian , Huixin Li , Zhenyu Liu , Guangchuan Wang , Xing-Can Shen , Ruikang Tang , Xiaoyu Wang","doi":"10.1016/j.biomaterials.2024.122703","DOIUrl":"10.1016/j.biomaterials.2024.122703","url":null,"abstract":"<div><p>An obstacle in current tumor immunotherapies lies in the challenge of achieving sustained and tumor-targeting T cell immunity, impeded by the limited antigen processing and cross-presentation of tumor antigens. Here, we propose a hydrogel-based multicellular immune factory within the body that autonomously converts tumor cells into an antitumor vaccine. Within the body, the scaffold, formed by a calcium-containing chitosan hydrogel complex (ChitoCa) entraps tumor cells and attracts immune cells to establish a durable and multicellular microenvironment. Within this context, tumor cells are completely eliminated by antigen-presenting cells (APCs) and processed for cross-antigen presentation. The regulatory mechanism relies on the Mincle receptor, a cell-phagocytosis-inducing C-type lectin receptor specifically activated on ChitoCa-recruited APCs, which serves as a recognition synapse, facilitating a tenfold increase in tumor cell engulfment and subsequent elimination. The ChitoCa-induced tumor cell processing further promotes the cross-presentation of tumor antigens to prime protective CD8<sup>+</sup> T cell responses. Therefore, the ChitoCa treatment establishes an immune niche within the tumor microenvironment, resulting in effective tumor regression either used alone or in combination with other immunotherapies. This hydrogel-induced immune factory establishes a functional organ-like multicellular colony for tumor-specific immunotherapy, paving the way for innovative strategies in cancer treatment.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602906","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 : 2024-07-06DOI: 10.1016/j.biomaterials.2024.122699
Caiping Yan , Pengrui Zhang , Qiwei Qin , Ke Jiang , Yue Luo , Chao Xiang , Jiangtao He , Lu Chen , Dianming Jiang , Wenguo Cui , Yuling Li
The treatment of osteoporotic bone defects poses a challenge due to the degradation of the skeletal vascular system and the disruption of local bone metabolism within the osteoporotic microenvironment. However, it is feasible to modulate the disrupted local bone metabolism imbalance through enhanced vascularization, a theory termed "vascularization-bone metabolic balance". This study developed a 3D-printed polycaprolactone (PCL) scaffold modified with EPLQLKM and SVVYGLR peptides (PCL-SE). The EPLQLKM peptide attracts bone marrow-derived mesenchymal stem cells (BMSCs), while the SVVYGLR peptide enhances endothelial progenitor cells (EPCs) vascular differentiation, thus regulating bone metabolism and fostering bone regeneration through the paracrine effects of EPCs. Further mechanistic research demonstrated that PCL-SE promoted the vascularization of EPCs, activating the Notch signaling pathway in BMSCs, leading to the upregulation of osteogenesis-related genes and the downregulation of osteoclast-related genes, thereby restoring bone metabolic balance. Furthermore, PCL-SE facilitated the differentiation of EPCs into "H"-type vessels and the recruitment of BMSCs to synergistically enhance osteogenesis, resulting in the regeneration of normal microvessels and bone tissues in cases of femoral condylar bone defects in osteoporotic SD rats. This study suggests that PCL-SE supports in-situ vascularization, remodels bone metabolic translational balance, and offers a promising therapeutic regimen for osteoporotic bone defects.
{"title":"3D-printed bone regeneration scaffolds modulate bone metabolic homeostasis through vascularization for osteoporotic bone defects","authors":"Caiping Yan , Pengrui Zhang , Qiwei Qin , Ke Jiang , Yue Luo , Chao Xiang , Jiangtao He , Lu Chen , Dianming Jiang , Wenguo Cui , Yuling Li","doi":"10.1016/j.biomaterials.2024.122699","DOIUrl":"10.1016/j.biomaterials.2024.122699","url":null,"abstract":"<div><p>The treatment of osteoporotic bone defects poses a challenge due to the degradation of the skeletal vascular system and the disruption of local bone metabolism within the osteoporotic microenvironment. However, it is feasible to modulate the disrupted local bone metabolism imbalance through enhanced vascularization, a theory termed \"vascularization-bone metabolic balance\". This study developed a 3D-printed polycaprolactone (PCL) scaffold modified with EPLQLKM and SVVYGLR peptides (PCL-SE). The EPLQLKM peptide attracts bone marrow-derived mesenchymal stem cells (BMSCs), while the SVVYGLR peptide enhances endothelial progenitor cells (EPCs) vascular differentiation, thus regulating bone metabolism and fostering bone regeneration through the paracrine effects of EPCs. Further mechanistic research demonstrated that PCL-SE promoted the vascularization of EPCs, activating the Notch signaling pathway in BMSCs, leading to the upregulation of osteogenesis-related genes and the downregulation of osteoclast-related genes, thereby restoring bone metabolic balance. Furthermore, PCL-SE facilitated the differentiation of EPCs into \"H\"-type vessels and the recruitment of BMSCs to synergistically enhance osteogenesis, resulting in the regeneration of normal microvessels and bone tissues in cases of femoral condylar bone defects in osteoporotic SD rats. This study suggests that PCL-SE supports in-situ vascularization, remodels bone metabolic translational balance, and offers a promising therapeutic regimen for osteoporotic bone defects.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562169","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 : 2024-07-06DOI: 10.1016/j.biomaterials.2024.122701
Lin Huang , Jiaoyang Zhu , Guochao Wu , Wei Xiong , Jie Feng , Chenggong Yan , Jing Yang , Zongheng Li , Qingdeng Fan , Bin Ren , Yan Li , Chaomin Chen , Xiangrong Yu , Zheyu Shen
Cuproptosis in antitumor therapy faces challenges from copper homeostasis efflux mechanisms and high glutathione (GSH) levels in tumor cells, hindering copper accumulation and treatment efficacy. Herein, we propose a strategy of “adding fuel to the flames” for potent antitumor therapy through a self-accelerating cycle of ferroptosis-cuproptosis. Disulfiram (DSF) loaded hollow mesoporous copper-iron sulfide (HMCIS) nanoparticle with conjugation of polyethylene glycol (PEG) and folic acid (FA) (i.e., DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, H2S, Cu2+, and Fe2+ in the acidic tumor microenvironment (TME). The hydrogen peroxide (H2O2) levels and acidity within tumor cells enhanced by the released H2S induce acceleration of Fenton (Fe2+) and Fenton-like (Cu2+) reactions, enabling the powerful tumor ferroptosis efficacy. The released DSF acts as a role of “fuel”, intensifying catalytic effect (“flame”) in tumor cells through the sustainable Fenton chemistry (i.e., “add fuel to the flames”). Robust ferroptosis in tumor cells is characterized by serious mitochondrial damage and GSH depletion, leading to excess intracellular copper that triggers cuproptosis. Cuproptosis disrupts mitochondria, compromises iron-sulfur (Fe–S) proteins, and elevates intracellular oxidative stress by releasing free Fe3+. These interconnected processes form a self-accelerating cycle of ferroptosis-cuproptosis with potent antitumor capabilities, as validated in both cancer cells and tumor-bearing mice.
{"title":"A strategy of “adding fuel to the flames” enables a self-accelerating cycle of ferroptosis-cuproptosis for potent antitumor therapy","authors":"Lin Huang , Jiaoyang Zhu , Guochao Wu , Wei Xiong , Jie Feng , Chenggong Yan , Jing Yang , Zongheng Li , Qingdeng Fan , Bin Ren , Yan Li , Chaomin Chen , Xiangrong Yu , Zheyu Shen","doi":"10.1016/j.biomaterials.2024.122701","DOIUrl":"10.1016/j.biomaterials.2024.122701","url":null,"abstract":"<div><p>Cuproptosis in antitumor therapy faces challenges from copper homeostasis efflux mechanisms and high glutathione (GSH) levels in tumor cells, hindering copper accumulation and treatment efficacy. Herein, we propose a strategy of “adding fuel to the flames” for potent antitumor therapy through a self-accelerating cycle of ferroptosis-cuproptosis. Disulfiram (DSF) loaded hollow mesoporous copper-iron sulfide (HMCIS) nanoparticle with conjugation of polyethylene glycol (PEG) and folic acid (FA) (<em>i.e.</em>, DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, H<sub>2</sub>S, Cu<sup>2+</sup>, and Fe<sup>2+</sup> in the acidic tumor microenvironment (TME). The hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) levels and acidity within tumor cells enhanced by the released H<sub>2</sub>S induce acceleration of Fenton (Fe<sup>2+</sup>) and Fenton-like (Cu<sup>2+</sup>) reactions, enabling the powerful tumor ferroptosis efficacy. The released DSF acts as a role of “fuel”, intensifying catalytic effect (“flame”) in tumor cells through the sustainable Fenton chemistry (<em>i.e.</em>, “add fuel to the flames”). Robust ferroptosis in tumor cells is characterized by serious mitochondrial damage and GSH depletion, leading to excess intracellular copper that triggers cuproptosis. Cuproptosis disrupts mitochondria, compromises iron-sulfur (Fe–S) proteins, and elevates intracellular oxidative stress by releasing free Fe<sup>3+</sup>. These interconnected processes form a self-accelerating cycle of ferroptosis-cuproptosis with potent antitumor capabilities, as validated in both cancer cells and tumor-bearing mice.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562170","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 : 2024-07-04DOI: 10.1016/j.biomaterials.2024.122700
Zhicheng Le , Mayk Caldas Ramos , Yufeng Shou , Renee R. Li , Hong Sheng Cheng , Clarisse JM. Jang , Ling Liu , Chencheng Xue , Xianlei Li , Hong Liu , Chwee Teck Lim , Nguan Soon Tan , Andrew D. White , Christopher John Charles , Yongming Chen , Zhijia Liu , Andy Tay
Impaired wound healing due to insufficient cell proliferation and angiogenesis is a significant physical and psychological burden to patients worldwide. Therapeutic delivery of exogenous growth factors (GFs) at high doses for wound repair is non-ideal as GFs have poor stability in proteolytic wound environments. Here, we present a two-stage strategy using bioactive sucralfate-based microneedle (SUC-MN) for delivering interleukin-4 (IL-4) to accelerate wound healing. In the first stage, SUC-MN synergistically enhanced the effect of IL-4 through more potent reprogramming of pro-regenerative M2-like macrophages via the JAK-STAT pathway to increase endogenous GF production. In the second stage, sucralfate binds to GFs and sterically disfavors protease degradation to increase bioavailability of GFs. The IL-4/SUC-MN technology accelerated wound healing by 56.6 % and 46.5 % in diabetic mice wounds and porcine wounds compared to their respective untreated controls. Overall, our findings highlight the innovative use of molecular simulations to identify bioactive ingredients and their incorporation into microneedles for promoting wound healing through multiple synergistic mechanisms.
{"title":"Bioactive sucralfate-based microneedles promote wound healing through reprogramming macrophages and protecting endogenous growth factors","authors":"Zhicheng Le , Mayk Caldas Ramos , Yufeng Shou , Renee R. Li , Hong Sheng Cheng , Clarisse JM. Jang , Ling Liu , Chencheng Xue , Xianlei Li , Hong Liu , Chwee Teck Lim , Nguan Soon Tan , Andrew D. White , Christopher John Charles , Yongming Chen , Zhijia Liu , Andy Tay","doi":"10.1016/j.biomaterials.2024.122700","DOIUrl":"https://doi.org/10.1016/j.biomaterials.2024.122700","url":null,"abstract":"<div><p>Impaired wound healing due to insufficient cell proliferation and angiogenesis is a significant physical and psychological burden to patients worldwide. Therapeutic delivery of exogenous growth factors (GFs) at high doses for wound repair is non-ideal as GFs have poor stability in proteolytic wound environments. Here, we present a two-stage strategy using bioactive sucralfate-based microneedle (SUC-MN) for delivering interleukin-4 (IL-4) to accelerate wound healing. In the first stage, SUC-MN synergistically enhanced the effect of IL-4 through more potent reprogramming of pro-regenerative M2-like macrophages via the JAK-STAT pathway to increase endogenous GF production. In the second stage, sucralfate binds to GFs and sterically disfavors protease degradation to increase bioavailability of GFs. The IL-4/SUC-MN technology accelerated wound healing by 56.6 % and 46.5 % in diabetic mice wounds and porcine wounds compared to their respective untreated controls. Overall, our findings highlight the innovative use of molecular simulations to identify bioactive ingredients and their incorporation into microneedles for promoting wound healing through multiple synergistic mechanisms.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141595756","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 : 2024-07-02DOI: 10.1016/j.biomaterials.2024.122697
Yumeng Yan , Xiaonan Huang , Lili Yuan , To Ngai , Guanghui Ma , Yufei Xia
The incorporation of molecular adjuvants has revolutionized vaccine by boosting overall immune efficacy. While traditional efforts have been concentrated on the quality and quantity of vaccine components, the impact of adjuvant and antigen delivery kinetics on immunity remains to be fully understood. Here, we employed poly (lactic-co-glycolic acid) nanoparticle (PLGA NP) -stabilized Pickering emulsion (PPE) to refine the delivery kinetics of molecular adjuvant CpG and antigen, aiming to optimize immune responses. The hierarchical structure of PPE enabled spatially differential loading of CpG and antigen. The component inserted on the oil-water interphase exhibited a rapid release profile, while the one encapsulated in the PLGA NPs demonstrated a sustained release. This led to distinct intracellular spatial-temporal release kinetics. Compared to the PPE with sustained CpG release and burst release of antigen, we found that the PPE with rapid CpG release and sustained antigen release triggered an early and robust activation of Toll-like receptor 9 (TLR9) in direct way. This fostered a more immunogenic microenvironment, significantly outperforming the inverted delivery profile in dendritic cells (DCs) activation, resulting in higher CD40 expression, elevated proinflammatory cytokine levels, sustained antigen cross-presentation, an enhanced Th1 response, and increased CD8+ T cells. Moreover, prior exposure of CpG led to suppressed tumor growth and enhanced efficacy in Varicella-zoster virus (VZV) vaccine. Our findings underscore the importance of tuning adjuvant and antigen delivery kinetics in vaccine design, proposing a novel path for enhancing vaccination outcomes.
分子佐剂的加入提高了疫苗的整体免疫效果,从而使疫苗发生了革命性的变化。传统的研究主要集中在疫苗成分的质量和数量上,而佐剂和抗原递送动力学对免疫的影响仍有待充分了解。在此,我们采用聚(乳酸-共聚-乙醇酸)纳米颗粒(PLGA NP)稳定皮克林乳液(PPE)来改进分子佐剂 CpG 和抗原的递送动力学,旨在优化免疫反应。PPE 的分层结构实现了 CpG 和抗原的空间差异化负载。插入油水相间层的成分表现出快速释放特性,而包裹在聚乳酸乙烯雌酚(PLGA)NPs 中的成分则表现出持续释放特性。这导致了不同的细胞内空间-时间释放动力学。与 CpG 持续释放和抗原猝发释放的 PPE 相比,我们发现 CpG 快速释放和抗原持续释放的 PPE 直接触发了 Toll 样受体 9 (TLR9) 的早期强激活。这促进了更多的免疫原性微环境,在树突状细胞(DCs)活化方面明显优于倒置递送模式,导致更高的 CD40 表达、促炎细胞因子水平升高、持续的抗原交叉呈递、Th1 反应增强以及 CD8+ T 细胞增加。此外,事先暴露 CpG 可抑制肿瘤生长并提高水痘-带状疱疹病毒(VZV)疫苗的疗效。我们的发现强调了在疫苗设计中调整佐剂和抗原递送动力学的重要性,为提高疫苗接种效果提出了一条新途径。
{"title":"Dictating the spatial-temporal delivery of molecular adjuvant and antigen for the enhanced vaccination","authors":"Yumeng Yan , Xiaonan Huang , Lili Yuan , To Ngai , Guanghui Ma , Yufei Xia","doi":"10.1016/j.biomaterials.2024.122697","DOIUrl":"10.1016/j.biomaterials.2024.122697","url":null,"abstract":"<div><p>The incorporation of molecular adjuvants has revolutionized vaccine by boosting overall immune efficacy. While traditional efforts have been concentrated on the quality and quantity of vaccine components, the impact of adjuvant and antigen delivery kinetics on immunity remains to be fully understood. Here, we employed poly (lactic-<em>co</em>-glycolic acid) nanoparticle (PLGA NP) -stabilized Pickering emulsion (PPE) to refine the delivery kinetics of molecular adjuvant CpG and antigen, aiming to optimize immune responses. The hierarchical structure of PPE enabled spatially differential loading of CpG and antigen. The component inserted on the oil-water interphase exhibited a rapid release profile, while the one encapsulated in the PLGA NPs demonstrated a sustained release. This led to distinct intracellular spatial-temporal release kinetics. Compared to the PPE with sustained CpG release and burst release of antigen, we found that the PPE with rapid CpG release and sustained antigen release triggered an early and robust activation of Toll-like receptor 9 (TLR9) in direct way. This fostered a more immunogenic microenvironment, significantly outperforming the inverted delivery profile in dendritic cells (DCs) activation, resulting in higher CD40 expression, elevated proinflammatory cytokine levels, sustained antigen cross-presentation, an enhanced Th1 response, and increased CD8<sup>+</sup> T cells. Moreover, prior exposure of CpG led to suppressed tumor growth and enhanced efficacy in Varicella-zoster virus (VZV) vaccine. Our findings underscore the importance of tuning adjuvant and antigen delivery kinetics in vaccine design, proposing a novel path for enhancing vaccination outcomes.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537156","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 : 2024-07-02DOI: 10.1016/j.biomaterials.2024.122698
Md Sohanur Rahaman , Asuva Arin , Ume Farwa , Myeongki Park , Sang Ho Bae , Byong-Taek Lee
Peptides and molecular residues sourced from the fragmentation of the extracellular matrix (ECM) can exacerbate a plethora of cellular functions. We selected a natural ECM-derived complex peptide mixture to functionalize sodium alginate. Three alginate derivatives (sodium alginate conjugated with ECM) SALE-1, SALE-2, and SALE-3 were synthesized using the lowest (10 % w/w), moderate (50 % w/w), and highest (100 % w/w) concentrations of ECM. Thereafter, they were used to fabricate three groups of mat scaffolds EMAT-1 (ECM derivatized alginate thrombin-mat), EMAT-2, and EMAT-3, respectively by the freeze-drying process. To enhance the hemostatic activity, thrombin was loaded onto the scaffolds. Another group, AT, without any derivatized alginate was additionally included in order to comparative analysis. Physical characteristics revealed that the porous mat scaffold showed enhancement in degradation and swelling ability with the increase in ECM content. The higher cell proliferation, migration, and cell viability were noticed in the higher ECM-containing samples EMAT-2 and EMAT-3. In vivo studies using rodent hepatic and rabbit ear models were carried out to ensure the hemostatic ability of the scaffolds. EMAT-2 and EMAT-3 demonstrate excellent liver regeneration ability in rat models. Moreover, the rat cutaneous wound model depicted that EMAT-3 dramatically elevated the skin's healing ability, thereby rendering it an excellent candidate for future clinical application in wound healing.
{"title":"ECM derivatized alginate augmenting bio-functionalities of lyophilized mat for skin and liver wound treatment","authors":"Md Sohanur Rahaman , Asuva Arin , Ume Farwa , Myeongki Park , Sang Ho Bae , Byong-Taek Lee","doi":"10.1016/j.biomaterials.2024.122698","DOIUrl":"10.1016/j.biomaterials.2024.122698","url":null,"abstract":"<div><p>Peptides and molecular residues sourced from the fragmentation of the extracellular matrix (ECM) can exacerbate a plethora of cellular functions. We selected a natural ECM-derived complex peptide mixture to functionalize sodium alginate. Three alginate derivatives (sodium alginate conjugated with ECM) SALE-1, SALE-2, and SALE-3 were synthesized using the lowest (10 % w/w), moderate (50 % w/w), and highest (100 % w/w) concentrations of ECM. Thereafter, they were used to fabricate three groups of mat scaffolds EMAT-1 (ECM derivatized alginate thrombin-mat), EMAT-2, and EMAT-3, respectively by the freeze-drying process. To enhance the hemostatic activity, thrombin was loaded onto the scaffolds. Another group, AT, without any derivatized alginate was additionally included in order to comparative analysis. Physical characteristics revealed that the porous mat scaffold showed enhancement in degradation and swelling ability with the increase in ECM content. The higher cell proliferation, migration, and cell viability were noticed in the higher ECM-containing samples EMAT-2 and EMAT-3. <em>In vivo</em> studies using rodent hepatic and rabbit ear models were carried out to ensure the hemostatic ability of the scaffolds. EMAT-2 and EMAT-3 demonstrate excellent liver regeneration ability in rat models. Moreover, the rat cutaneous wound model depicted that EMAT-3 dramatically elevated the skin's healing ability, thereby rendering it an excellent candidate for future clinical application in wound healing.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537157","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 : 2024-07-02DOI: 10.1016/j.biomaterials.2024.122696
Yujun Zhang , Shijing Wang , Hyeonji Rha , Chang Xu , Yue Pei , Xiaoyuan Ji , Junmin Zhang , Ruitao Lu , Shaochong Zhang , Zhongjian Xie , Jong Seung Kim
Cancer immunotherapy has been developed to improve therapeutic effects for patients by activating the innate immune stimulator of interferon gene (STING) pathway. However, most patients cannot benefit from this therapy, mainly due to the problems of excessively low immune responses and lack of tumor specificity. Herein, we report a solution to these two problems by developing a bifunctional platform of black phosphorus quantum dots (BPQDs) for STING agonists. Specifically, BPQDs could connect targeted functional groups and regulate surface zeta potential by coordinating metal ions to increase loading (over 5 times) while maintaining high universality (7 STING agonists). The controlled release of STING agonists enabled specific interactions with their proteins, activating the STING pathway and stimulating the secretion release of immunosuppressive factors by phosphorylating TBK1 and IFN-IRF3 and secreting high levels of immunostimulatory cytokines, including IL-6, IFN-α, and IFN-β. Moreover, the immunotherapy was enhanced was enhanced mild photothermal therapy (PTT) of BPQDs platform, producing enough T cells to eliminate tumors and prevent tumor recurrence. This work facilitates further research on targeted delivery of small-molecule immune drugs to enhance the development of clinical immunotherapy.
{"title":"Bifunctional black phosphorus quantum dots platform: Delivery and remarkable immunotherapy enhancement of STING agonist","authors":"Yujun Zhang , Shijing Wang , Hyeonji Rha , Chang Xu , Yue Pei , Xiaoyuan Ji , Junmin Zhang , Ruitao Lu , Shaochong Zhang , Zhongjian Xie , Jong Seung Kim","doi":"10.1016/j.biomaterials.2024.122696","DOIUrl":"https://doi.org/10.1016/j.biomaterials.2024.122696","url":null,"abstract":"<div><p>Cancer immunotherapy has been developed to improve therapeutic effects for patients by activating the innate immune stimulator of interferon gene (STING) pathway. However, most patients cannot benefit from this therapy, mainly due to the problems of excessively low immune responses and lack of tumor specificity. Herein, we report a solution to these two problems by developing a bifunctional platform of black phosphorus quantum dots (BPQDs) for STING agonists. Specifically, BPQDs could connect targeted functional groups and regulate surface zeta potential by coordinating metal ions to increase loading (over 5 times) while maintaining high universality (7 STING agonists). The controlled release of STING agonists enabled specific interactions with their proteins, activating the STING pathway and stimulating the secretion release of immunosuppressive factors by phosphorylating TBK1 and IFN-IRF3 and secreting high levels of immunostimulatory cytokines, including IL-6, IFN-α, and IFN-β. Moreover, the immunotherapy was enhanced was enhanced mild photothermal therapy (PTT) of BPQDs platform, producing enough T cells to eliminate tumors and prevent tumor recurrence. This work facilitates further research on targeted delivery of small-molecule immune drugs to enhance the development of clinical immunotherapy.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141542728","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 : 2024-07-01DOI: 10.1016/j.biomaterials.2024.122691
Changcan Li , Gang Xu , Yinhan Wang , Laixin Huang , Feiyan Cai , Long Meng , Bao Jin , Zhuoran Jiang , Hang Sun , Haitao Zhao , Xin Lu , Xingting Sang , Pengyu Huang , Fei Li , Huayu Yang , Yilei Mao , Hairong Zheng
Acoustic holography (AH), a promising approach for cell patterning, emerges as a powerful tool for constructing novel invitro 3D models that mimic organs and cancers features. However, understanding changes in cell function post-AH remains limited. Furthermore, replicating complex physiological and pathological processes solely with cell lines proves challenging. Here, we employed acoustical holographic lattice to assemble primary hepatocytes directly isolated from mice into a cell cluster matrix to construct a liver-shaped tissue sample. For the first time, we evaluated the liver functions of AH-patterned primary hepatocytes. The patterned model exhibited large numbers of self-assembled spheroids and superior multifarious core hepatocyte functions compared to cells in 2D and traditional 3D culture models. AH offers a robust protocol for long-term in vitro culture of primary cells, underscoring its potential for future applications in disease pathogenesis research, drug testing, and organ replacement therapy.
{"title":"Acoustic-holography-patterned primary hepatocytes possess liver functions","authors":"Changcan Li , Gang Xu , Yinhan Wang , Laixin Huang , Feiyan Cai , Long Meng , Bao Jin , Zhuoran Jiang , Hang Sun , Haitao Zhao , Xin Lu , Xingting Sang , Pengyu Huang , Fei Li , Huayu Yang , Yilei Mao , Hairong Zheng","doi":"10.1016/j.biomaterials.2024.122691","DOIUrl":"https://doi.org/10.1016/j.biomaterials.2024.122691","url":null,"abstract":"<div><p>Acoustic holography (AH), a promising approach for cell patterning, emerges as a powerful tool for constructing novel <em>in</em> <em>vitro</em> 3D models that mimic organs and cancers features. However, understanding changes in cell function post-AH remains limited. Furthermore, replicating complex physiological and pathological processes solely with cell lines proves challenging. Here, we employed acoustical holographic lattice to assemble primary hepatocytes directly isolated from mice into a cell cluster matrix to construct a liver-shaped tissue sample. For the first time, we evaluated the liver functions of AH-patterned primary hepatocytes. The patterned model exhibited large numbers of self-assembled spheroids and superior multifarious core hepatocyte functions compared to cells in 2D and traditional 3D culture models. AH offers a robust protocol for long-term <em>in vitro</em> culture of primary cells, underscoring its potential for future applications in disease pathogenesis research, drug testing, and organ replacement therapy.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0142961224002254/pdfft?md5=df7c51c3136205eda686cebecf4e5623&pid=1-s2.0-S0142961224002254-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141595732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-29DOI: 10.1016/j.biomaterials.2024.122695
Pengfei Zhang , Di Zhong , Yongbo Yu , Lupeng Wang , Yifan Li , Ye Liang , Yanfeng Shi , Meilin Duan , Bing Li , Haitao Niu , Yuanhong Xu
Integrating immunotherapy with nanomaterials-based chemotherapy presents a promising avenue for amplifying antitumor outcomes. Nevertheless, the suppressive tumor immune microenvironment (TIME) and the upregulation of cyclooxygenase-2 (COX-2) induced by chemotherapy can hinder the efficacy of the chemoimmunotherapy. This study presents a TIME-reshaping strategy by developing a steric-hindrance effect tuned zinc-based metal-organic framework (MOF), designated as CZFNPs. This nanoreactor is engineered by in situ loading of the COX-2 inhibitor, C-phycocyanin (CPC), into the framework building blocks, while simultaneously weakening the stability of the MOF. Consequently, CZFNPs achieve rapid pH-responsive release of zinc ions (Zn2+) and CPC upon specific transport to tumor cells overexpressing folate receptors. Accordingly, Zn2+ can induce reactive oxygen species (ROS)-mediated cytotoxicity therapy while synchronize with mitochondrial DNA (mtDNA) release, which stimulates mtDNA/cGAS-STING pathway-mediated innate immunity. The CPC suppresses the chemotherapy-induced overexpression of COX-2, thus cooperatively reprogramming the suppressive TIME and boosting the antitumor immune response. In xenograft tumor models, the CZFNPs system effectively modulates STING and COX-2 expression, converting “cold” tumors into “hot” tumors, thereby resulting in ≈ 4-fold tumor regression relative to ZIF-8 treatment alone. This approach offers a potent strategy for enhancing the efficacy of combined nanomaterial-based chemotherapy and immunotherapy.
{"title":"Integration of STING activation and COX-2 inhibition via steric-hindrance effect tuned nanoreactors for cancer chemoimmunotherapy","authors":"Pengfei Zhang , Di Zhong , Yongbo Yu , Lupeng Wang , Yifan Li , Ye Liang , Yanfeng Shi , Meilin Duan , Bing Li , Haitao Niu , Yuanhong Xu","doi":"10.1016/j.biomaterials.2024.122695","DOIUrl":"https://doi.org/10.1016/j.biomaterials.2024.122695","url":null,"abstract":"<div><p>Integrating immunotherapy with nanomaterials-based chemotherapy presents a promising avenue for amplifying antitumor outcomes. Nevertheless, the suppressive tumor immune microenvironment (TIME) and the upregulation of cyclooxygenase-2 (COX-2) induced by chemotherapy can hinder the efficacy of the chemoimmunotherapy. This study presents a TIME-reshaping strategy by developing a steric-hindrance effect tuned zinc-based metal-organic framework (MOF), designated as CZFNPs. This nanoreactor is engineered by in situ loading of the COX-2 inhibitor, C-phycocyanin (CPC), into the framework building blocks, while simultaneously weakening the stability of the MOF. Consequently, CZFNPs achieve rapid pH-responsive release of zinc ions (Zn<sup>2+</sup>) and CPC upon specific transport to tumor cells overexpressing folate receptors. Accordingly, Zn<sup>2+</sup> can induce reactive oxygen species (ROS)-mediated cytotoxicity therapy while synchronize with mitochondrial DNA (mtDNA) release, which stimulates mtDNA/cGAS-STING pathway-mediated innate immunity. The CPC suppresses the chemotherapy-induced overexpression of COX-2, thus cooperatively reprogramming the suppressive TIME and boosting the antitumor immune response. In xenograft tumor models, the CZFNPs system effectively modulates STING and COX-2 expression, converting “cold” tumors into “hot” tumors, thereby resulting in ≈ 4-fold tumor regression relative to ZIF-8 treatment alone. This approach offers a potent strategy for enhancing the efficacy of combined nanomaterial-based chemotherapy and immunotherapy.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141482085","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}