Pub Date : 2024-10-22DOI: 10.1016/j.biomaterials.2024.122910
Qi-Song Tong , Hua Huang , Hui-Han Yu , Rong Liu , Song Shen , Jin-Zhi Du
Remodeling the immunosuppressive tumor microenvironment (TME) by immunomodulators has been well studied in the past years. However, strategies that enable concurrent modulation of both the immunosuppressive TME and tumor-draining lymph nodes (TDLNs) are still in the infancy. Here, we report a pH-sensitive size-switchable nanocluster, SPN-R848, to achieve simultaneous accumulation in tumor and TDLNs for immune activation. SPN-R848 with original size around 150 nm was formed by self-assembly of resiquimod (R848)-conjugated polyamidoamine (PAMAM) derivative, which could disintegrate into its small constituents (～ 8 nm) upon exposure to tumor acidity. The size reduction not only enhanced their accumulation and perfusion in the primary tumor, but promoted their transport and distribution in TDLNs. Accordingly, SPN-R848 remarkably remodeled the immunosuppressive TME by polarizing M2 to M1 macrophages and activated dendritic cells (DCs) in TDLNs, which synergistically facilitated the production and stimulation of cytotoxic T cells, and inhibited tumor growth in breast cancer and melanoma mouse models. Our study suggests that co-activation of immune microenvironments in both tumor and TDLNs may represent a promising direction to elicit strong antitumor immunity.
{"title":"A size-switchable nanocluster remodels the immunosuppressive microenvironment of tumor and tumor-draining lymph nodes for improved cancer immunotherapy","authors":"Qi-Song Tong , Hua Huang , Hui-Han Yu , Rong Liu , Song Shen , Jin-Zhi Du","doi":"10.1016/j.biomaterials.2024.122910","DOIUrl":"10.1016/j.biomaterials.2024.122910","url":null,"abstract":"<div><div>Remodeling the immunosuppressive tumor microenvironment (TME) by immunomodulators has been well studied in the past years. However, strategies that enable concurrent modulation of both the immunosuppressive TME and tumor-draining lymph nodes (TDLNs) are still in the infancy. Here, we report a pH-sensitive size-switchable nanocluster, SPN-R848, to achieve simultaneous accumulation in tumor and TDLNs for immune activation. SPN-R848 with original size around 150 nm was formed by self-assembly of resiquimod (R848)-conjugated polyamidoamine (PAMAM) derivative, which could disintegrate into its small constituents (～ 8 nm) upon exposure to tumor acidity. The size reduction not only enhanced their accumulation and perfusion in the primary tumor, but promoted their transport and distribution in TDLNs. Accordingly, SPN-R848 remarkably remodeled the immunosuppressive TME by polarizing M2 to M1 macrophages and activated dendritic cells (DCs) in TDLNs, which synergistically facilitated the production and stimulation of cytotoxic T cells, and inhibited tumor growth in breast cancer and melanoma mouse models. Our study suggests that co-activation of immune microenvironments in both tumor and TDLNs may represent a promising direction to elicit strong antitumor immunity.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122910"},"PeriodicalIF":12.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520568","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 : 2024-10-22DOI: 10.1016/j.biomaterials.2024.122914
Bin Fang , Hua Bai , Jiaxin Zhang , Limin Wang , PanPan Li , Yihao Ge , Hui Yang , Hui Wang , Bo Peng , Wenbo Hu , Huili Ma , Xi Chen , Li Fu , Lin Li
Tumor ablation Preclinical organelle-targeted phototherapies have effectively achieved tumor photoablation for regenerative biomedical applications in cancer therapies. However, engineering effective phototherapy drugs with precise tumor-localization targeting and organelle direction remains challenging. Herein, we report a albumins constrainting mitochondrial-targeted photosensitizer nanoparticles (PSs@BSAs) for tumor-specific photodynamic therapy. X-ray crystallography elucidates the two-stage assembly mechanism of PSs@BSAs. Femtosecond transient absorption spectroscopy and quantum mechanical calculations reveal the implications of conformational dynamics at the excited state. PSs@BSAs can efficiently disable mitochondrial activity, and further disrupt tumor angiogenesis based on the photodynamic effect. This triggers a metabolic and oxidative stress crisis to facilitate photoablation of solid tumor and antitumor metastasis. The study fully elucidates the interdisciplinary issues of chemistry, physics, and biological interfaces, thereby opening new horizons to inspire the engineering of organelle-targeted tumor-specific photosensitizers for biomedical applications.
{"title":"Albumins constrainting the conformation of mitochondria-targeted photosensitizers for tumor-specific photodynamic therapy","authors":"Bin Fang , Hua Bai , Jiaxin Zhang , Limin Wang , PanPan Li , Yihao Ge , Hui Yang , Hui Wang , Bo Peng , Wenbo Hu , Huili Ma , Xi Chen , Li Fu , Lin Li","doi":"10.1016/j.biomaterials.2024.122914","DOIUrl":"10.1016/j.biomaterials.2024.122914","url":null,"abstract":"<div><div>Tumor ablation Preclinical organelle-targeted phototherapies have effectively achieved tumor photoablation for regenerative biomedical applications in cancer therapies. However, engineering effective phototherapy drugs with precise tumor-localization targeting and organelle direction remains challenging. Herein, we report a albumins constrainting mitochondrial-targeted photosensitizer nanoparticles (PSs@BSAs) for tumor-specific photodynamic therapy. X-ray crystallography elucidates the two-stage assembly mechanism of PSs@BSAs. Femtosecond transient absorption spectroscopy and quantum mechanical calculations reveal the implications of conformational dynamics at the excited state. PSs@BSAs can efficiently disable mitochondrial activity, and further disrupt tumor angiogenesis based on the photodynamic effect. This triggers a metabolic and oxidative stress crisis to facilitate photoablation of solid tumor and antitumor metastasis. The study fully elucidates the interdisciplinary issues of chemistry, physics, and biological interfaces, thereby opening new horizons to inspire the engineering of organelle-targeted tumor-specific photosensitizers for biomedical applications.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122914"},"PeriodicalIF":12.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491866","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 : 2024-10-22DOI: 10.1016/j.biomaterials.2024.122912
Guangqiang Li , Ruolin Zhang , Keyu Chen , Jiawen Dong , Zhihao Yang , Hangyu Chen , Haipeng Wang , Hui Wang , Huali Lei , Wendai Bao , Min Zhang , Zhidong Xiao , Liang Cheng , Zhiqiang Dong
Stroke is one of the leading causes of death and disability in the world. Ischemic stroke causes overproduction of reactive oxygen/nitrogen species (RONS) after reperfusion, triggering inflammatory responses that further leads to cell damage. In order to develop novel neuroprotective materials, we synthesized zinc sulfide nanoparticles (ZnS NPs) to function as gas slow-release bioreactors, showcasing stable and sustained H2S release while effectively removing RONS. In cultured cells, ZnS NPs can reduce the oxidative damage caused by oxygen-glucose deprivation and reoxygenation (OGD/R), promote the expression of p-AMPK, enhance microglia M2 polarization, decrease inflammatory factors and reduce neuronal apoptosis. Additionally, it increases the proliferation and migration of endothelial cells, promoting the formation of new neurovascular units by regulating the protein of p-AKT. In mice with ischemic stroke induced by middle cerebral artery occlusion/reperfusion (MCAO/R), ZnS NPs significantly reduce the infarct area and restore the mobility of mice owing to the slow release of H2S. In summary, our results indicate that ZnS NPs can be used as H2S slow-release bioreactors, offering a potentially innovative approach to treat ischemia-reperfusion injury caused by stroke.
{"title":"Zinc sulfide nanoparticles serve as gas slow-release bioreactors for H2S therapy of ischemic stroke","authors":"Guangqiang Li , Ruolin Zhang , Keyu Chen , Jiawen Dong , Zhihao Yang , Hangyu Chen , Haipeng Wang , Hui Wang , Huali Lei , Wendai Bao , Min Zhang , Zhidong Xiao , Liang Cheng , Zhiqiang Dong","doi":"10.1016/j.biomaterials.2024.122912","DOIUrl":"10.1016/j.biomaterials.2024.122912","url":null,"abstract":"<div><div>Stroke is one of the leading causes of death and disability in the world. Ischemic stroke causes overproduction of reactive oxygen/nitrogen species (RONS) after reperfusion, triggering inflammatory responses that further leads to cell damage. In order to develop novel neuroprotective materials, we synthesized zinc sulfide nanoparticles (ZnS NPs) to function as gas slow-release bioreactors, showcasing stable and sustained H<sub>2</sub>S release while effectively removing RONS. In cultured cells, ZnS NPs can reduce the oxidative damage caused by oxygen-glucose deprivation and reoxygenation (OGD/R), promote the expression of p-AMPK, enhance microglia M2 polarization, decrease inflammatory factors and reduce neuronal apoptosis. Additionally, it increases the proliferation and migration of endothelial cells, promoting the formation of new neurovascular units by regulating the protein of p-AKT. In mice with ischemic stroke induced by middle cerebral artery occlusion/reperfusion (MCAO/R), ZnS NPs significantly reduce the infarct area and restore the mobility of mice owing to the slow release of H<sub>2</sub>S. In summary, our results indicate that ZnS NPs can be used as H<sub>2</sub>S slow-release bioreactors, offering a potentially innovative approach to treat ischemia-reperfusion injury caused by stroke.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122912"},"PeriodicalIF":12.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142529312","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 : 2024-10-22DOI: 10.1016/j.biomaterials.2024.122909
Guang Shi , Shenghui Lan , Qi Zhang , Junwu Wang , Feihong Shu , Zhuowen Hao , Tianhong Chen , Mengyue Zhu , Renxin Chen , Jiayao Chen , Zijian Wu , Bo Wu , Zhenwei Zou , Jingfeng Li
Osteoarthritis (OA) manifests as the degradation of cartilage and remodeling of subchondral bone. Restoring homeostasis within the joint is imperative for alleviating OA symptoms. Current interventions primarily target singular aspects, such as anti-aging, inflammation inhibition, free radical scavenging, and regeneration of cartilage and subchondral bone. Herein, we developed molybdenum nanodots (MNDs) as bionic photothermal nanomaterials to mimic the antioxidant synthase to concurrently protected cartilage and facilitate subchondral bone regeneration. With near-infrared (NIR) irradiation, MNDs effectively eliminate reactive oxygen and nitrogen species (ROS/RNS) from OA chondrocytes, thereby reversed mitochondrial dysfunction, mitigating chondrocyte senescence, and simultaneously suppresses inflammation, hence preserving the inherent homeostasis between cartilage matrix synthesis and degradation while circumventing safety concerns. RNA sequencing of OA chondrocytes treated with MNDs-NIR revealed the reinstatement of chondrocyte functionality, activation of antioxidant enzymes, anti-aging properties, and regulation of inflammation. NIR irradiation induces thermogenesis and synergistically promotes subchondral bone regeneration via MNDs, as validated through histological assessments and microcomputed tomography (Micro-CT) scans. MNDs-NIR effectively attenuate cellular senescence and inhibit inflammation in vivo, while also remodeling mitochondrial dynamics by upregulating fusion proteins and inhibiting fission proteins, thereby regulating the oxidative stress microenvironment. Additionally, MNDs-NIR exhibited remarkable therapeutic effects in alleviating articular cartilage degeneration in an OA mouse model, evidenced by a 1.67-fold reduction in subchondral bone plate thickness, an 88.57 % decrease in OARSI score, a 5.52-fold reduction in MMP13 expression, and a 6.80-fold increase in Col II expression. This novel disease-modifying approach for OA utilizing MNDs-NIR offers insight and a paradigm for improving mitochondrial dysfunction by regulating the accumulation of mitochondrial ROS and ultimately alleviating cellular senescence. Moreover, the dual-pronged therapeutic approach of MNDs-NIR, which addresses both cartilage erosion and subchondral bone lesions in OA, represents a highly promising strategy for managing OA.
骨关节炎（OA）表现为软骨退化和软骨下骨重塑。要缓解 OA 症状，必须恢复关节内的平衡。目前的干预措施主要针对单一方面，如抗衰老、抑制炎症、清除自由基以及软骨和软骨下骨的再生。在此，我们开发了仿生光热纳米材料钼纳米点（MNDs）来模拟抗氧化合成酶，从而同时保护软骨和促进软骨下骨再生。在近红外（NIR）照射下，MNDs能有效消除OA软骨细胞中的活性氧和氮物种（ROS/RNS），从而逆转线粒体功能障碍，缓解软骨细胞衰老，并同时抑制炎症，从而保持软骨基质合成和降解之间的内在平衡，同时规避安全问题。用 MNDs-NIR 处理 OA 软骨细胞的 RNA 测序显示，软骨细胞的功能得到恢复，抗氧化酶被激活，具有抗衰老特性，并能调节炎症。通过组织学评估和微计算机断层扫描（Micro-CT）验证，近红外辐照可诱导产热，并通过 MNDs 协同促进软骨下骨再生。MNDs-NIR 能有效减轻细胞衰老并抑制体内炎症，同时还能通过上调融合蛋白和抑制裂变蛋白重塑线粒体动力学，从而调节氧化应激微环境。此外，MNDs-NIR 在减轻 OA 小鼠模型的关节软骨退化方面表现出显著的治疗效果，软骨下骨板厚度减少了 1.67 倍，OARSI 评分降低了 88.57%，MMP13 表达减少了 5.52 倍，Col II 表达增加了 6.80 倍。这种利用 MNDs-NIR 治疗 OA 的新型疾病调节方法为通过调节线粒体 ROS 的积累来改善线粒体功能障碍并最终缓解细胞衰老提供了见解和范例。此外，MNDs-NIR 的双管齐下治疗方法可同时解决 OA 中的软骨侵蚀和软骨下骨病变问题，是一种极具前景的治疗 OA 的策略。
{"title":"Molybdenum nanodots act as antioxidants for photothermal therapy osteoarthritis","authors":"Guang Shi , Shenghui Lan , Qi Zhang , Junwu Wang , Feihong Shu , Zhuowen Hao , Tianhong Chen , Mengyue Zhu , Renxin Chen , Jiayao Chen , Zijian Wu , Bo Wu , Zhenwei Zou , Jingfeng Li","doi":"10.1016/j.biomaterials.2024.122909","DOIUrl":"10.1016/j.biomaterials.2024.122909","url":null,"abstract":"<div><div>Osteoarthritis (OA) manifests as the degradation of cartilage and remodeling of subchondral bone. Restoring homeostasis within the joint is imperative for alleviating OA symptoms. Current interventions primarily target singular aspects, such as anti-aging, inflammation inhibition, free radical scavenging, and regeneration of cartilage and subchondral bone. Herein, we developed molybdenum nanodots (MNDs) as bionic photothermal nanomaterials to mimic the antioxidant synthase to concurrently protected cartilage and facilitate subchondral bone regeneration. With near-infrared (NIR) irradiation, MNDs effectively eliminate reactive oxygen and nitrogen species (ROS/RNS) from OA chondrocytes, thereby reversed mitochondrial dysfunction, mitigating chondrocyte senescence, and simultaneously suppresses inflammation, hence preserving the inherent homeostasis between cartilage matrix synthesis and degradation while circumventing safety concerns. RNA sequencing of OA chondrocytes treated with MNDs-NIR revealed the reinstatement of chondrocyte functionality, activation of antioxidant enzymes, anti-aging properties, and regulation of inflammation. NIR irradiation induces thermogenesis and synergistically promotes subchondral bone regeneration via MNDs, as validated through histological assessments and microcomputed tomography (Micro-CT) scans. MNDs-NIR effectively attenuate cellular senescence and inhibit inflammation in vivo, while also remodeling mitochondrial dynamics by upregulating fusion proteins and inhibiting fission proteins, thereby regulating the oxidative stress microenvironment. Additionally, MNDs-NIR exhibited remarkable therapeutic effects in alleviating articular cartilage degeneration in an OA mouse model, evidenced by a 1.67-fold reduction in subchondral bone plate thickness, an 88.57 % decrease in OARSI score, a 5.52-fold reduction in MMP13 expression, and a 6.80-fold increase in Col II expression. This novel disease-modifying approach for OA utilizing MNDs-NIR offers insight and a paradigm for improving mitochondrial dysfunction by regulating the accumulation of mitochondrial ROS and ultimately alleviating cellular senescence. Moreover, the dual-pronged therapeutic approach of MNDs-NIR, which addresses both cartilage erosion and subchondral bone lesions in OA, represents a highly promising strategy for managing OA.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122909"},"PeriodicalIF":12.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542449","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}
Fungal infections affect over 13 million people worldwide and are responsible for 1.5 million deaths annually. Some deep cutaneous fungal infections may extend the dermal barriers to cause systemic infection, resulting in substantial morbidity and mortality. However, the management of deep cutaneous fungal infection is challenging and yet overlooked by traditional treatments, which only offer limited drug availability within deep tissue. In this study, we have developed an electrically stimulated microneedle patch to deliver miconazole into the subcutaneous layer. We tested its antifungal efficacy using in vitro and ex vivo models that mimic fungal infection. Moreover, we confirmed its anti-fungal and wound-healing effects in a murine subcutaneous fungal infection model. Furthermore, our findings also showed that the combination of miconazole and applied current synergistically stimulated the nociceptive sensory nerves, thereby activating protective cutaneous immunity mediated by dermal dendritic and γδ-T cells. Collectively, this study provides a new strategy for minimally invasive delivery of therapeutic agents and the modulation of the neuro-immune axis in deep tissue.
{"title":"Electrically-driven drug delivery into deep cutaneous tissue by conductive microneedles for fungal infection eradication and protective immunity","authors":"Sumanta Ghosh , Mengjia Zheng , Jiahui He , Yefeng Wu , Yaming Zhang , Weiping Wang , Jie Shen , Kelvin W.K. Yeung , Prasanna Neelakantan , Chenjie Xu , Wei Qiao","doi":"10.1016/j.biomaterials.2024.122908","DOIUrl":"10.1016/j.biomaterials.2024.122908","url":null,"abstract":"<div><div>Fungal infections affect over 13 million people worldwide and are responsible for 1.5 million deaths annually. Some deep cutaneous fungal infections may extend the dermal barriers to cause systemic infection, resulting in substantial morbidity and mortality. However, the management of deep cutaneous fungal infection is challenging and yet overlooked by traditional treatments, which only offer limited drug availability within deep tissue. In this study, we have developed an electrically stimulated microneedle patch to deliver miconazole into the subcutaneous layer. We tested its antifungal efficacy using <em>in vitro</em> and <em>ex vivo</em> models that mimic fungal infection. Moreover, we confirmed its anti-fungal and wound-healing effects in a murine subcutaneous fungal infection model. Furthermore, our findings also showed that the combination of miconazole and applied current synergistically stimulated the nociceptive sensory nerves, thereby activating protective cutaneous immunity mediated by dermal dendritic and γδ-T cells. Collectively, this study provides a new strategy for minimally invasive delivery of therapeutic agents and the modulation of the neuro-immune axis in deep tissue.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122908"},"PeriodicalIF":12.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491859","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 : 2024-10-21DOI: 10.1016/j.biomaterials.2024.122905
Shuai Guo , Tianwang Guan , Yushen Ke , Yuping Lin, Rundong Tai, Jujian Ye, Zhilin Deng, Shaohui Deng, Caiwen Ou
Amidst the therapeutic quandaries associated with triple-negative breast cancer (TNBC), an aggressive malignancy distinguished by its immune resistance and limited treatment avenues, the urgent need for innovative solutions is underscored. To conquer the dilemma, we present a groundbreaking approach that ingeniously employs DNA-fragments-containing exosomes (DNA-Exo) and the concept of “biological logic-gates” to achieve precise homing and controlled selective activation of ferroptosis and stimulator interferon genes (STING) pathways. Leveraging insights from our previous research, a nano-Trojan-horse, Fe0@HMON@DNA-Exo, is engineered via in situ Fe0 synthesis within the glutathione (GSH)-responsiveness degradable hollow mesoporous organosilica nanoparticles (HMON) and subsequently enveloped in DNA-Exo derived from 7-ethyl-10-hydroxycamptothecin (SN38)-treated 4T1 cells. Emphasizing the precision of our approach, the DNA-Exo ensures specific ‘homing’ to TNBC cells, rendering a targeted delivery mechanism. Concurrently, the concept of “biological logic-gates” is employed to dictate a meticulous and selective activation of STING in antigen-presenting cells (APCs) under OR logic-gating with robust immune response and Fe0-based ferroptosis in TNBC cells under AND logic-gating with reactive oxygen species (ROS) storm generation. In essence, our strategy exhibits great potential in transforming the “immunologically cold” nature of TNBC, enabling precise control over cellular responses, illuminating a promising therapeutic paradigm that is comprehensive and productive in pursuing precision oncology and paving the way for personalized TNBC therapies.
三阴性乳腺癌（TNBC）是一种侵袭性恶性肿瘤，具有免疫耐受和治疗途径有限的特点，与之相关的治疗难题凸显了对创新解决方案的迫切需求。为了解决这一难题，我们提出了一种开创性的方法，它巧妙地利用了含DNA片段的外泌体（DNA-Exo）和 "生物逻辑门 "的概念，实现了精确的归巢和铁突变及刺激干扰素基因（STING）通路的可控选择性激活。利用我们之前研究的洞察力，通过在谷胱甘肽（GSH）反应性可降解中空介孔有机硅纳米粒子（HMON）内原位合成Fe0，然后将其包裹在来自7-乙基-10-羟基喜树碱（SN38）处理过的4T1细胞的DNA-Exo中，设计出了一种纳米特洛伊木马--Fe0@HMON@DNA-Exo。DNA-Exo确保了TNBC细胞的特异性 "归巢"，从而提供了一种靶向递送机制，强调了我们方法的精确性。同时，我们还采用了 "生物逻辑门 "的概念，在 OR 逻辑门的作用下，抗原递呈细胞（APCs）中的 STING 被细致而有选择性地激活，从而产生强有力的免疫反应；在 AND 逻辑门的作用下，TNBC 细胞中的铁氧化酶（Fe0-based ferroptosis）被激活，从而产生活性氧（ROS）风暴。从本质上讲，我们的策略在改变 TNBC 的 "免疫冷漠 "特性、实现对细胞反应的精确控制方面展现出巨大潜力，为追求精准肿瘤学和为 TNBC 个性化疗法铺平道路提供了一个全面而富有成效的治疗范例。
{"title":"Biologically logic-gated Trojan-horse strategy for personalized triple-negative breast cancer precise therapy by selective ferroptosis and STING pathway provoking","authors":"Shuai Guo , Tianwang Guan , Yushen Ke , Yuping Lin, Rundong Tai, Jujian Ye, Zhilin Deng, Shaohui Deng, Caiwen Ou","doi":"10.1016/j.biomaterials.2024.122905","DOIUrl":"10.1016/j.biomaterials.2024.122905","url":null,"abstract":"<div><div>Amidst the therapeutic quandaries associated with triple-negative breast cancer (TNBC), an aggressive malignancy distinguished by its immune resistance and limited treatment avenues, the urgent need for innovative solutions is underscored. To conquer the dilemma, we present a groundbreaking approach that ingeniously employs DNA-fragments-containing exosomes (DNA-Exo) and the concept of “biological logic-gates” to achieve precise homing and controlled selective activation of ferroptosis and stimulator interferon genes (STING) pathways. Leveraging insights from our previous research, a nano-Trojan-horse, Fe<sup>0</sup>@HMON@DNA-Exo, is engineered <em>via in situ</em> Fe<sup>0</sup> synthesis within the glutathione (GSH)-responsiveness degradable hollow mesoporous organosilica nanoparticles (HMON) and subsequently enveloped in DNA-Exo derived from 7-ethyl-10-hydroxycamptothecin (SN38)-treated 4T1 cells. Emphasizing the precision of our approach, the DNA-Exo ensures specific ‘homing’ to TNBC cells, rendering a targeted delivery mechanism. Concurrently, the concept of “biological logic-gates” is employed to dictate a meticulous and selective activation of STING in antigen-presenting cells (APCs) under OR logic-gating with robust immune response and Fe<sup>0</sup>-based ferroptosis in TNBC cells under AND logic-gating with reactive oxygen species (ROS) storm generation. In essence, our strategy exhibits great potential in transforming the “immunologically cold” nature of TNBC, enabling precise control over cellular responses, illuminating a promising therapeutic paradigm that is comprehensive and productive in pursuing precision oncology and paving the way for personalized TNBC therapies.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122905"},"PeriodicalIF":12.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142538496","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 : 2024-10-21DOI: 10.1016/j.biomaterials.2024.122894
Ke Gao , Wenjin Xi , Jianxin Ni , Jun Jiang , Yonghua Lei , Lin Li , Jie Chu , Ruixiao Li , Yongpan An , Yanan Ouyang , Ruiping Su , Rui Zhang , Guojun Wu
Prostate cancer (PCa) is associated with poor immunogenicity and lymphocytic infiltration, and immunotherapy effective against PCa remains unavailable. Pyroptosis, a novel immunotherapeutic modality for cancer, promotes systemic immune responses leading to immunogenic cell death in solid tumors. This paper describes the preparation and analysis of PSMAscFv-EVN-GSDMD; this genetically engineered recombinant extracellular vesicle (EV) expresses a single-chain variable antibody fragment (scFv) with high affinity for prostate-specific membrane antigen (PSMA) on their surfaces and is loaded with the N-terminal domain of gasdermin D (GSDMD). Both in vitro and in vivo, PSMAscFv-EVN-GSDMD effectively targeted PSMA-positive PCa cells and induced pyroptosis through the carrier properties of EVs and the specificity of PSMAscFv. In the 22RV1 and PSMA-transfected RM-1-inoculated PCa mouse models, PSMAscFv-EVN-GSDMD efficiently inhibited tumor growth and promoted tumor immune responses. In conclusion, PSMAscFv-EVN-GSDMD can convert the immunosuppressive “cold” tumor microenvironment of PCa into an immunogenic “hot” tumor microenvironment.
{"title":"Genetically modified extracellular vesicles loaded with activated gasdermin D potentially inhibit prostate-specific membrane antigen-positive prostate carcinoma growth and enhance immunotherapy","authors":"Ke Gao , Wenjin Xi , Jianxin Ni , Jun Jiang , Yonghua Lei , Lin Li , Jie Chu , Ruixiao Li , Yongpan An , Yanan Ouyang , Ruiping Su , Rui Zhang , Guojun Wu","doi":"10.1016/j.biomaterials.2024.122894","DOIUrl":"10.1016/j.biomaterials.2024.122894","url":null,"abstract":"<div><div>Prostate cancer (PCa) is associated with poor immunogenicity and lymphocytic infiltration, and immunotherapy effective against PCa remains unavailable. Pyroptosis, a novel immunotherapeutic modality for cancer, promotes systemic immune responses leading to immunogenic cell death in solid tumors. This paper describes the preparation and analysis of PSMA<sub>scFv</sub>-EV<sup>N-GSDMD</sup>; this genetically engineered recombinant extracellular vesicle (EV) expresses a single-chain variable antibody fragment (scFv) with high affinity for prostate-specific membrane antigen (PSMA) on their surfaces and is loaded with the N-terminal domain of gasdermin D (GSDMD). Both in vitro and in vivo, PSMA<sub>scFv</sub>-EV<sup>N-GSDMD</sup> effectively targeted PSMA-positive PCa cells and induced pyroptosis through the carrier properties of EVs and the specificity of PSMA<sub>scFv</sub>. In the 22RV1 and PSMA-transfected RM-1-inoculated PCa mouse models, PSMA<sub>scFv</sub>-EV<sup>N-GSDMD</sup> efficiently inhibited tumor growth and promoted tumor immune responses. In conclusion, PSMA<sub>scFv</sub>-EV<sup>N-GSDMD</sup> can convert the immunosuppressive “cold” tumor microenvironment of PCa into an immunogenic “hot” tumor microenvironment.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122894"},"PeriodicalIF":12.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491867","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 : 2024-10-20DOI: 10.1016/j.biomaterials.2024.122900
Jiranuwat Sapudom , Aseel Alatoom , Paul Sean Tipay , Jeremy CM. Teo
T-cells are essential components of the immune system, adapting their behavior in response to the mechanical environments they encounter within the body. In pathological conditions like cancer, the extracellular matrix (ECM) often becomes stiffer due to increased density and alignment of collagen fibrils, which can have a significant impact on T-cell function. In this study, we explored how these ECM properties—density and fibrillar alignment—affect T-cell behavior using three-dimensional (3D) collagen matrices that mimic these conditions. Our results show that increased matrix stiffness, whether due to higher density or alignment, significantly suppresses T-cell activation, reduces cytokine production, and limits proliferation, largely through enhanced YAP signaling. Individually, matrix alignment appears to lower actin levels in activated T-cells and changes migration behavior in both resting and activated T-cells, an effect not observed in matrices with randomly oriented fibrils. Notably, inhibiting YAP signaling was able to restore T-cell activation and improve immune responses, suggesting a potential strategy to boost the effectiveness of immunotherapy in stiff ECM environments. Overall, this study provides new insights into how ECM characteristics influence T-cell function, offering potential avenues for overcoming ECM-induced immunosuppression in diseases such as cancer.
T 细胞是免疫系统的重要组成部分，它们会根据在体内遇到的机械环境调整自己的行为。在癌症等病理情况下，细胞外基质（ECM）往往会因为胶原纤维密度和排列的增加而变得更加坚硬，这可能会对 T 细胞的功能产生重大影响。在这项研究中，我们利用三维（3D）胶原蛋白基质模拟这些情况，探索了这些 ECM 特性（密度和纤维排列）如何影响 T 细胞的行为。我们的研究结果表明，基质刚度的增加（无论是由于密度增加还是排列整齐）会显著抑制 T 细胞的活化、减少细胞因子的产生并限制其增殖，这主要是通过 YAP 信号的增强来实现的。单独来看，基质排列似乎会降低活化T细胞的肌动蛋白水平，并改变静止和活化T细胞的迁移行为，而这种效应在随机定向纤维的基质中观察不到。值得注意的是，抑制 YAP 信号传导能恢复 T 细胞活化并改善免疫反应，这表明在僵硬的 ECM 环境中提高免疫疗法效果的潜在策略是可行的。总之，这项研究提供了关于 ECM 特性如何影响 T 细胞功能的新见解，为克服癌症等疾病中 ECM 诱导的免疫抑制提供了潜在的途径。
{"title":"Matrix stiffening from collagen fibril density and alignment modulates YAP-mediated T-cell immune suppression","authors":"Jiranuwat Sapudom , Aseel Alatoom , Paul Sean Tipay , Jeremy CM. Teo","doi":"10.1016/j.biomaterials.2024.122900","DOIUrl":"10.1016/j.biomaterials.2024.122900","url":null,"abstract":"<div><div>T-cells are essential components of the immune system, adapting their behavior in response to the mechanical environments they encounter within the body. In pathological conditions like cancer, the extracellular matrix (ECM) often becomes stiffer due to increased density and alignment of collagen fibrils, which can have a significant impact on T-cell function. In this study, we explored how these ECM properties—density and fibrillar alignment—affect T-cell behavior using three-dimensional (3D) collagen matrices that mimic these conditions. Our results show that increased matrix stiffness, whether due to higher density or alignment, significantly suppresses T-cell activation, reduces cytokine production, and limits proliferation, largely through enhanced YAP signaling. Individually, matrix alignment appears to lower actin levels in activated T-cells and changes migration behavior in both resting and activated T-cells, an effect not observed in matrices with randomly oriented fibrils. Notably, inhibiting YAP signaling was able to restore T-cell activation and improve immune responses, suggesting a potential strategy to boost the effectiveness of immunotherapy in stiff ECM environments. Overall, this study provides new insights into how ECM characteristics influence T-cell function, offering potential avenues for overcoming ECM-induced immunosuppression in diseases such as cancer.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122900"},"PeriodicalIF":12.8,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491868","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 : 2024-10-19DOI: 10.1016/j.biomaterials.2024.122895
Yuanyuan Jin , Jiabin Zhang , Xiaodie Chen , Fenfang Li , Tiantian Xue , Ke Yi , Yanteng Xu , Haixia Wang , Yeh-Hsing Lao , Hon Fai Chan , Dan Shao , Mingqiang Li , Yu Tao
Acute liver failure (ALF) is a highly fatal disease, necessitating the advancement and optimization of alternative therapeutic strategies to benefit patients awaiting liver transplantation. In this study, we innovatively established the antioxidant nanozyme-hepatocyte-like cells (HLCs) microtissue sheets (HS/N–Au@composite) for ALF therapy. We first prepared a 3D-printed hyaluronic acid/gelatin/sodium alginate scaffold with N-acetylcysteine (NAC)-capped gold nanoclusters (NAC-Au NCs), forming the N–Au@hydrogel. For the encapsulation of HLC spheroids, we used a biocompatible hybrid hydrogel composed of decellularized extracellular matrix (dECM), thrombin, and fibrinogen, resulting in the HS@dECM hydrogel. Utilizing 3D printing technology, we integrated the N–Au@hydrogel with the HS@dECM hydrogel to create the HS/N–Au@composite for in situ transplantation to treat ALF. Our results demonstrated that NAC-Au NCs effectively mitigated reactive oxygen species (ROS)-induced liver necrosis in ALF. Additionally, the N–Au@hydrogel provided mechanical support, ensuring the proper landing and effective functioning of the transplanted HLC spheroids. The HS/N–Au@composite synergistically decreased serum transaminase levels, reduced the accumulation of pro-inflammatory cytokines, accelerated liver function recovery, and promoted liver regeneration in ALF treatment. This combination of HLC spheroids and NAC-Au NCs nanozymes via 3D-printed composite scaffolds represents a promising strategy for enhancing hepatocyte transplantation and advancing stem cell regenerative medicine in ALF therapy.
{"title":"3D printing incorporating gold nanozymes with mesenchymal stem cell-derived hepatic spheroids for acute liver failure treatment","authors":"Yuanyuan Jin , Jiabin Zhang , Xiaodie Chen , Fenfang Li , Tiantian Xue , Ke Yi , Yanteng Xu , Haixia Wang , Yeh-Hsing Lao , Hon Fai Chan , Dan Shao , Mingqiang Li , Yu Tao","doi":"10.1016/j.biomaterials.2024.122895","DOIUrl":"10.1016/j.biomaterials.2024.122895","url":null,"abstract":"<div><div>Acute liver failure (ALF) is a highly fatal disease, necessitating the advancement and optimization of alternative therapeutic strategies to benefit patients awaiting liver transplantation. In this study, we innovatively established the antioxidant nanozyme-hepatocyte-like cells (HLCs) microtissue sheets (HS/N–Au@composite) for ALF therapy. We first prepared a 3D-printed hyaluronic acid/gelatin/sodium alginate scaffold with N-acetylcysteine (NAC)-capped gold nanoclusters (NAC-Au NCs), forming the N–Au@hydrogel. For the encapsulation of HLC spheroids, we used a biocompatible hybrid hydrogel composed of decellularized extracellular matrix (dECM), thrombin, and fibrinogen, resulting in the HS@dECM hydrogel. Utilizing 3D printing technology, we integrated the N–Au@hydrogel with the HS@dECM hydrogel to create the HS/N–Au@composite for in situ transplantation to treat ALF. Our results demonstrated that NAC-Au NCs effectively mitigated reactive oxygen species (ROS)-induced liver necrosis in ALF. Additionally, the N–Au@hydrogel provided mechanical support, ensuring the proper landing and effective functioning of the transplanted HLC spheroids. The HS/N–Au@composite synergistically decreased serum transaminase levels, reduced the accumulation of pro-inflammatory cytokines, accelerated liver function recovery, and promoted liver regeneration in ALF treatment. This combination of HLC spheroids and NAC-Au NCs nanozymes via 3D-printed composite scaffolds represents a promising strategy for enhancing hepatocyte transplantation and advancing stem cell regenerative medicine in ALF therapy.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"315 ","pages":"Article 122895"},"PeriodicalIF":12.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491865","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 : 2024-10-19DOI: 10.1016/j.biomaterials.2024.122902
Hyunjun Choi , Bongseo Choi , Dong-Hyun Kim
Anaerobic bacteriolytic cancer therapy, whether delivered locally or systemically, frequently encounters challenges related to limited colonization within hypoxic pockets of central tumors and activation of innate immunity. Herein we have developed trans-arterial bacteria embolization therapy using bacterial embolic microspheres. C. novyi-NT spores loaded calcium alginate embolic microspheres demonstrated C. novyi-NT metabolites-mediated microsphere degradation, releasing vegetative C. novyi-NT bacterial in hypoxic condition. Transcatheter directed bacterial microsphere embolization therapy occludes tumor feeding vessels with infused bacterial embolic microspheres and enhances tumoral hypoxia. Notably, anaerobic bacterial metabolism responsive microsphere-bacterial embolization therapy achieved a complete tumor response with enhanced tumor-specific bacterial delivery and colonization, resulting in cancer cell killing across the entire tumor. In vivo tumor response and immunological profiling revealed that bacterial embolization uniquely enhances anti-cancer response, effectively engaging direct anaerobic bacterial oncolysis and adaptive and innate immune responses in a cooperative manner.
{"title":"Anaerobic bacterial metabolism responsive microspheres for bacterial embolization cancer therapy","authors":"Hyunjun Choi , Bongseo Choi , Dong-Hyun Kim","doi":"10.1016/j.biomaterials.2024.122902","DOIUrl":"10.1016/j.biomaterials.2024.122902","url":null,"abstract":"<div><div>Anaerobic bacteriolytic cancer therapy, whether delivered locally or systemically, frequently encounters challenges related to limited colonization within hypoxic pockets of central tumors and activation of innate immunity. Herein we have developed trans-arterial bacteria embolization therapy using bacterial embolic microspheres. <em>C. novyi</em>-NT spores loaded calcium alginate embolic microspheres demonstrated <em>C. novyi</em>-NT metabolites-mediated microsphere degradation, releasing vegetative <em>C. novyi</em>-NT bacterial in hypoxic condition. Transcatheter directed bacterial microsphere embolization therapy occludes tumor feeding vessels with infused bacterial embolic microspheres and enhances tumoral hypoxia. Notably, anaerobic bacterial metabolism responsive microsphere-bacterial embolization therapy achieved a complete tumor response with enhanced tumor-specific bacterial delivery and colonization, resulting in cancer cell killing across the entire tumor. <em>In vivo</em> tumor response and immunological profiling revealed that bacterial embolization uniquely enhances anti-cancer response, effectively engaging direct anaerobic bacterial oncolysis and adaptive and innate immune responses in a cooperative manner.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"314 ","pages":"Article 122902"},"PeriodicalIF":12.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491858","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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