Single-cell transcriptomics and high-throughput transcriptomics were used to screen factors significantly correlated with intervertebral disc degeneration (IDD). Expression changes of CFIm25 were determined via RT-qPCR and Western blot. NP cells were isolated from mouse intervertebral discs and induced to degrade with TNF-α and IL-1β. CFIm25 was knocked out using CRISPR-Cas9, and CFIm25 knockout and overexpressing nucleus pulposus (NP) cell lines were generated through lentiviral transfection. Proteoglycan expression, protein expression, inflammatory factor expression, cell viability, proliferation, migration, gene expression, and protein expression were analyzed using various assays (alcian blue staining, immunofluorescence, ELISA, CCK-8, EDU labeling, transwell migration, scratch assay, RT-qPCR, Western blot). The GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA was designed, and its effects on NP regeneration were assessed through in vitro and mouse model experiments. The progression of IDD in mice was evaluated using X-ray, H&E staining, and Safranin O-Fast Green staining. Immunohistochemistry was performed to determine protein expression in NP tissue. Proteomic analysis combined with in vitro and in vivo experiments was conducted to elucidate the mechanisms of hydrogel action. CFIm25 was upregulated in IDD NP tissue and significantly correlated with disease progression. Inhibition of CFIm25 improved NP cell degeneration, enhanced cell proliferation, and migration. The hydrogel effectively knocked down CFIm25 expression, improved NP cell degeneration, promoted cell proliferation and migration, and mitigated IDD progression in a mouse model. The hydrogel inhibited inflammatory factor expression (IL-6, iNOS, IL-1β, TNF-α) by targeting the p38/NF-κB signaling pathway, increased collagen COLII and proteoglycan Aggrecan expression, and suppressed NP degeneration-related factors (COX-2, MMP-3). The study highlighted the crucial role of CFIm25 in IDD and introduced a promising therapeutic strategy using a porous spherical GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA. This innovative approach offers new possibilities for treating degenerated intervertebral discs.
{"title":"A novel spherical GelMA-HAMA hydrogel encapsulating APET×2 polypeptide and CFIm25-targeting sgRNA for immune microenvironment modulation and nucleus pulposus regeneration in intervertebral discs","authors":"Xiao-Jun Yu, Yuan-Ting Zhao, Haimiti Abudouaini, Peng Zou, Tian-Qi Li, Xiao-Fan Bai, Shan-Xi Wang, Jian-Bin Guan, Meng-wei Li, Xiao-dong Wang, Ying-guang Wang, Ding-Jun Hao","doi":"10.1186/s12951-024-02783-z","DOIUrl":"https://doi.org/10.1186/s12951-024-02783-z","url":null,"abstract":"Single-cell transcriptomics and high-throughput transcriptomics were used to screen factors significantly correlated with intervertebral disc degeneration (IDD). Expression changes of CFIm25 were determined via RT-qPCR and Western blot. NP cells were isolated from mouse intervertebral discs and induced to degrade with TNF-α and IL-1β. CFIm25 was knocked out using CRISPR-Cas9, and CFIm25 knockout and overexpressing nucleus pulposus (NP) cell lines were generated through lentiviral transfection. Proteoglycan expression, protein expression, inflammatory factor expression, cell viability, proliferation, migration, gene expression, and protein expression were analyzed using various assays (alcian blue staining, immunofluorescence, ELISA, CCK-8, EDU labeling, transwell migration, scratch assay, RT-qPCR, Western blot). The GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA was designed, and its effects on NP regeneration were assessed through in vitro and mouse model experiments. The progression of IDD in mice was evaluated using X-ray, H&E staining, and Safranin O-Fast Green staining. Immunohistochemistry was performed to determine protein expression in NP tissue. Proteomic analysis combined with in vitro and in vivo experiments was conducted to elucidate the mechanisms of hydrogel action. CFIm25 was upregulated in IDD NP tissue and significantly correlated with disease progression. Inhibition of CFIm25 improved NP cell degeneration, enhanced cell proliferation, and migration. The hydrogel effectively knocked down CFIm25 expression, improved NP cell degeneration, promoted cell proliferation and migration, and mitigated IDD progression in a mouse model. The hydrogel inhibited inflammatory factor expression (IL-6, iNOS, IL-1β, TNF-α) by targeting the p38/NF-κB signaling pathway, increased collagen COLII and proteoglycan Aggrecan expression, and suppressed NP degeneration-related factors (COX-2, MMP-3). The study highlighted the crucial role of CFIm25 in IDD and introduced a promising therapeutic strategy using a porous spherical GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA. This innovative approach offers new possibilities for treating degenerated intervertebral discs. ","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Breast cancer therapy has significantly advanced by targeting the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway. BMS-202 (a smallmolecule PD-L1 inhibitor) induces PD-L1 dimerization to block PD-1/PD-L1 interactions, allowing the T-cell-mediated immune response to kill tumor cells. However, immunotherapy alone has limited effects. Clinically approved photodynamic therapy (PDT) activates immunity and selectively targets malignant cells. However, PDT aggravates hypoxia, which may compromise its therapeutic efficacy and promote tumor metastasis. We designed a tumor-specific delivery nanoplatform of liposomes that encapsulate the hypoxia-sensitive antitumor drug tirapazamine (TPZ) and the small-molecule immunosuppressant BMS. New indocyanine green (IR820)-loaded polyethylenimine-folic acid (PEI-FA) was complexed with TPZ and BMS-loaded liposomes via electrostatic interactions to form lipid nanocomposites. This nanoplatform can be triggered by near-infrared irradiation to induce PDT, resulting in a hypoxic tumor environment and activation of the prodrug TPZ to achieve efficient chemotherapy. The in vitro and in vivo studies demonstrated excellent combined PDT, chemotherapy, and immunotherapy effects on the regression of distant tumors and lung metastases, providing a reference method for the preparation of targeted agents for treating breast cancer.
{"title":"Preparation and effects of functionalized liposomes targeting breast cancer tumors using chemotherapy, phototherapy, and immunotherapy","authors":"Bowen Zeng, Lina Pian, Yanhong Liu, Shuangqing Wang, Nuoya Wang, Chao Liu, Hao Wu, Hongshuang Wan, Liqing Chen, Wei Huang, Zhonggao Gao, Xuezhe Yin, Mingji Jin","doi":"10.1186/s12951-024-02838-1","DOIUrl":"https://doi.org/10.1186/s12951-024-02838-1","url":null,"abstract":"Breast cancer therapy has significantly advanced by targeting the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway. BMS-202 (a smallmolecule PD-L1 inhibitor) induces PD-L1 dimerization to block PD-1/PD-L1 interactions, allowing the T-cell-mediated immune response to kill tumor cells. However, immunotherapy alone has limited effects. Clinically approved photodynamic therapy (PDT) activates immunity and selectively targets malignant cells. However, PDT aggravates hypoxia, which may compromise its therapeutic efficacy and promote tumor metastasis. We designed a tumor-specific delivery nanoplatform of liposomes that encapsulate the hypoxia-sensitive antitumor drug tirapazamine (TPZ) and the small-molecule immunosuppressant BMS. New indocyanine green (IR820)-loaded polyethylenimine-folic acid (PEI-FA) was complexed with TPZ and BMS-loaded liposomes via electrostatic interactions to form lipid nanocomposites. This nanoplatform can be triggered by near-infrared irradiation to induce PDT, resulting in a hypoxic tumor environment and activation of the prodrug TPZ to achieve efficient chemotherapy. The in vitro and in vivo studies demonstrated excellent combined PDT, chemotherapy, and immunotherapy effects on the regression of distant tumors and lung metastases, providing a reference method for the preparation of targeted agents for treating breast cancer. ","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1186/s12951-024-02827-4
Yixuan Wu, Hongyi Bao, Jinran Wu, Bairong Chen, Jing Xu, Kangfeng Jin, Lin Chen, Guang Zhu, Feng Wang
An increasing body of evidence suggests that acylphosphatase-2 (ACYP2) polymorphisms are correlated with an increased susceptibility to a range of malignancies. Nevertheless, its potential functions, molecular mechanisms in hepatocellular carcinoma (HCC) and whether it can be act as a therapeutic target remain uninvestigated. Herein, ACYP2 was found to be lowly expressed in HCC and was negatively correlated with tumor size, tumor differentiation, microvascular invasion and the prognosis of HCC patients. Functional investigations revealed that overexpression of ACYP2 inhibited the proliferation and metastasis of HCC cells while promoting apoptosis; knockdown of ACYP2 had the exact opposite effect. Additionally, it was observed that ACYP2 was distributed in both the cytoplasm and nucleus of HCC cells. According to the mechanistic studies, the expression of potassium calcium-activated channel subfamily N member 4 (KCNN4) was negatively regulated by cytoplasmic ACYP2, resulting in the inhibition of K+ outflow and subsequent inactivation of the ERK pathway, which impeded the growth and metastasis of HCC. Furthermore, the activity of telomerase reverse transcriptase (TERT) was inhibited by nuclear ACYP2, leading to the reduction in length of telomeres and consequent reversal of HCC cell immortalization. Additionally, a novel targeted nanotherapy strategy was developed wherein the pcDNA-ACYP2 vector was encapsulated within polyetherimide nanoparticles (PEI/NPs), which were subsequently coated with HCC cell membranes (namely pcDNA/PEI/NPs@M). Safety and targeting characteristics abound for these nanocomposites, in both subcutaneous graft tumor models and orthotopic mouse models, they inhibited the progression of HCC by impeding TERT activity and the KCNN4/ERK pathway. In conclusion, our research identifies novel molecular mechanisms involving cytoplasmic and nuclear ACYP2 that inhibit the progression of HCC. Moreover, pcDNA/PEI/NPs@M represents a targeted therapeutic strategy for HCC that holds great promising.
{"title":"ACYP2 functions as an innovative nano-therapeutic target to impede the progression of hepatocellular carcinoma by inhibiting the activity of TERT and the KCNN4/ERK pathway","authors":"Yixuan Wu, Hongyi Bao, Jinran Wu, Bairong Chen, Jing Xu, Kangfeng Jin, Lin Chen, Guang Zhu, Feng Wang","doi":"10.1186/s12951-024-02827-4","DOIUrl":"https://doi.org/10.1186/s12951-024-02827-4","url":null,"abstract":"An increasing body of evidence suggests that acylphosphatase-2 (ACYP2) polymorphisms are correlated with an increased susceptibility to a range of malignancies. Nevertheless, its potential functions, molecular mechanisms in hepatocellular carcinoma (HCC) and whether it can be act as a therapeutic target remain uninvestigated. Herein, ACYP2 was found to be lowly expressed in HCC and was negatively correlated with tumor size, tumor differentiation, microvascular invasion and the prognosis of HCC patients. Functional investigations revealed that overexpression of ACYP2 inhibited the proliferation and metastasis of HCC cells while promoting apoptosis; knockdown of ACYP2 had the exact opposite effect. Additionally, it was observed that ACYP2 was distributed in both the cytoplasm and nucleus of HCC cells. According to the mechanistic studies, the expression of potassium calcium-activated channel subfamily N member 4 (KCNN4) was negatively regulated by cytoplasmic ACYP2, resulting in the inhibition of K+ outflow and subsequent inactivation of the ERK pathway, which impeded the growth and metastasis of HCC. Furthermore, the activity of telomerase reverse transcriptase (TERT) was inhibited by nuclear ACYP2, leading to the reduction in length of telomeres and consequent reversal of HCC cell immortalization. Additionally, a novel targeted nanotherapy strategy was developed wherein the pcDNA-ACYP2 vector was encapsulated within polyetherimide nanoparticles (PEI/NPs), which were subsequently coated with HCC cell membranes (namely pcDNA/PEI/NPs@M). Safety and targeting characteristics abound for these nanocomposites, in both subcutaneous graft tumor models and orthotopic mouse models, they inhibited the progression of HCC by impeding TERT activity and the KCNN4/ERK pathway. In conclusion, our research identifies novel molecular mechanisms involving cytoplasmic and nuclear ACYP2 that inhibit the progression of HCC. Moreover, pcDNA/PEI/NPs@M represents a targeted therapeutic strategy for HCC that holds great promising. ","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1186/s12951-024-02771-3
Fei Guo, Yizhan Wu, Jiangwei Liu
The exacerbation of extreme high-temperature events due to global climate change poses a significant challenge to public health, particularly impacting the central nervous system through heat stroke. This study aims to develop Poly(amidoamine) (PAMAM) nanoparticles loaded with curcumin (PAMAM@Cur) to enhance its therapeutic efficacy in hypothalamic neural damage in a heat stroke model and explore its potential mechanisms. Curcumin (Cur) was encapsulated into PAMAM nanoparticles through a hydrophobic interaction method, and various techniques were employed to characterize their physicochemical properties. A heat stroke mouse model was established to monitor body temperature and serum biochemical parameters, conduct behavioral assessments, histological examinations, and biochemical analyses. Transcriptomic and proteomic analyses were performed to investigate the therapeutic mechanisms of PAMAM@Cur, validated in an N2a cell model. PAMAM@Cur demonstrated good stability, photostability, cell compatibility, significant blood–brain barrier (BBB) penetration capability, and effective accumulation in the brain. PAMAM@Cur markedly improved behavioral performance and neural cell structural integrity in heat stroke mice, alleviated inflammatory responses, with superior therapeutic effects compared to Cur or PAMAM alone. Multi-omics analysis revealed that PAMAM@Cur regulated antioxidant defense genes and iron death-related genes, particularly upregulating the PCBP2 protein, stabilizing SLC7A11 and GPX4 mRNA, and reducing iron-dependent cell death. By enhancing the drug delivery properties of Cur and modulating molecular pathways relevant to disease treatment, PAMAM@Cur significantly enhances the therapeutic effects against hypothalamic neural damage induced by heat stroke, showcasing the potential of nanotechnology in improving traditional drug efficacy and providing new strategies for future clinical applications. This study highlights the outlook of nanotechnology in treating neurological disorders caused by heat stroke, offering a novel therapeutic approach with potential clinical applications.
全球气候变化导致极端高温事件加剧，给公共卫生带来了重大挑战，尤其是中暑对中枢神经系统的影响。本研究旨在开发负载姜黄素（PAMAM@Cur）的聚酰胺胺（PAMAM）纳米粒子，以增强其在中暑模型中对下丘脑神经损伤的疗效，并探索其潜在机制。通过疏水相互作用方法将姜黄素（Cur）封装到 PAMAM 纳米颗粒中，并采用多种技术表征其理化性质。建立中暑小鼠模型，监测体温和血清生化指标，进行行为评估、组织学检查和生化分析。为了研究 PAMAM@Cur 的治疗机制，还进行了转录组和蛋白质组分析，并在 N2a 细胞模型中进行了验证。PAMAM@Cur表现出良好的稳定性、光稳定性、细胞相容性、显著的血脑屏障（BBB）穿透能力以及在大脑中的有效蓄积。PAMAM@Cur 显著改善了中暑小鼠的行为表现和神经细胞结构的完整性，缓解了炎症反应，治疗效果优于单独使用 Cur 或 PAMAM。多组学分析表明，PAMAM@Cur能调节抗氧化防御基因和铁死亡相关基因，特别是上调PCBP2蛋白，稳定SLC7A11和GPX4 mRNA，减少铁依赖性细胞死亡。PAMAM@Cur 通过增强 Cur 的给药特性和调节与疾病治疗相关的分子通路，显著提高了对中暑引起的下丘脑神经损伤的治疗效果，展示了纳米技术在改善传统药物疗效方面的潜力，并为未来的临床应用提供了新的策略。这项研究强调了纳米技术在治疗中暑引起的神经系统疾病方面的前景，提供了一种具有潜在临床应用价值的新型治疗方法。
{"title":"Curcumin nanoparticles in heat stroke management","authors":"Fei Guo, Yizhan Wu, Jiangwei Liu","doi":"10.1186/s12951-024-02771-3","DOIUrl":"https://doi.org/10.1186/s12951-024-02771-3","url":null,"abstract":"The exacerbation of extreme high-temperature events due to global climate change poses a significant challenge to public health, particularly impacting the central nervous system through heat stroke. This study aims to develop Poly(amidoamine) (PAMAM) nanoparticles loaded with curcumin (PAMAM@Cur) to enhance its therapeutic efficacy in hypothalamic neural damage in a heat stroke model and explore its potential mechanisms. Curcumin (Cur) was encapsulated into PAMAM nanoparticles through a hydrophobic interaction method, and various techniques were employed to characterize their physicochemical properties. A heat stroke mouse model was established to monitor body temperature and serum biochemical parameters, conduct behavioral assessments, histological examinations, and biochemical analyses. Transcriptomic and proteomic analyses were performed to investigate the therapeutic mechanisms of PAMAM@Cur, validated in an N2a cell model. PAMAM@Cur demonstrated good stability, photostability, cell compatibility, significant blood–brain barrier (BBB) penetration capability, and effective accumulation in the brain. PAMAM@Cur markedly improved behavioral performance and neural cell structural integrity in heat stroke mice, alleviated inflammatory responses, with superior therapeutic effects compared to Cur or PAMAM alone. Multi-omics analysis revealed that PAMAM@Cur regulated antioxidant defense genes and iron death-related genes, particularly upregulating the PCBP2 protein, stabilizing SLC7A11 and GPX4 mRNA, and reducing iron-dependent cell death. By enhancing the drug delivery properties of Cur and modulating molecular pathways relevant to disease treatment, PAMAM@Cur significantly enhances the therapeutic effects against hypothalamic neural damage induced by heat stroke, showcasing the potential of nanotechnology in improving traditional drug efficacy and providing new strategies for future clinical applications. This study highlights the outlook of nanotechnology in treating neurological disorders caused by heat stroke, offering a novel therapeutic approach with potential clinical applications. ","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1186/s12951-024-02795-9
Jiangyi Wu, Jinhui Wu, Wei Xiang, Yunquan Gong, Daibo Feng, Shunzheng Fang, Yaran Wu, Zheng Liu, Yang Li, Ran Chen, Xiaoqi Zhang, Bingfei Li, Lifeng Chen, Runze Jin, Song Li, Bin Zhang, Tongyi Zhang, Lin Yin, Yizhao Zhou, Shu Huang, Ningning Liu, Hao Xu, Jiqin Lian, Yongqian Wang, Siru Zhou, Zhenhong Ni
The pathogenesis of osteoarthritis (OA) involves the progressive degradation of articular cartilage. Exosomes derived from mesenchymal stem cells (MSC-EXOs) have been shown to mitigate joint pathological injury by attenuating cartilage destruction. Optimization the yield and therapeutic efficacy of exosomes derived from MSCs is crucial for promoting their clinical translation. The preconditioning of MSCs enhances the therapeutic potential of engineered exosomes, offering promising prospects for application by enabling controlled and quantifiable external stimulation. This study aims to address these issues by employing pro-inflammatory preconditioning of MSCs to enhance exosome production and augment their therapeutic efficacy for OA. The exosomes were isolated from the supernatant of infrapatellar fat pad (IPFP)-MSCs preconditioned with a pro-inflammatory factor, TNF-α, and their production was subsequently quantified. The exosome secretion-related pathways in IPFP-MSCs were evaluated through high-throughput transcriptome sequencing analysis, q-PCR and western blot analysis before and after TNF-α preconditioning. Furthermore, exosomes derived from TNF-α preconditioned IPFP-MSCs (IPFP-MSC-EXOsTNF−α) were administered intra-articularly in an OA mouse model, and subsequent evaluations were conducted to assess joint pathology and gait alterations. The expression of proteins involved in the maintenance of cartilage homeostasis within the exosomes was determined through proteomic analysis. The preconditioning with TNF-α significantly enhanced the exosome secretion of IPFP-MSCs compared to unpreconditioned MSCs. The potential mechanism involved the activation of the PI3K/AKT signaling pathway in IPFP-MSCs by TNF-α precondition, leading to an up-regulation of autophagy-related protein 16 like 1(ATG16L1) levels, which subsequently facilitated exosome secretion. The intra-articular administration of IPFP-MSC-EXOsTNF−α demonstrated superior efficacy in ameliorating pathological changes in the joints of OA mice. The preconditioning of TNF-α enhanced the up-regulation of low-density lipoprotein receptor-related protein 1 (LRP1) levels in IPFP-MSC-EXOsTNF−α, thereby exerting chondroprotective effects. TNF-α preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of IPFP-MSCs derived exosomes in the treatment of OA.
骨关节炎（OA）的发病机制包括关节软骨的逐渐退化。从间充质干细胞中提取的外泌体（MSC-EXOs）已被证明可通过减轻软骨破坏来减轻关节病理损伤。优化间充质干细胞外泌体的产量和疗效对促进其临床转化至关重要。间充质干细胞的预处理可增强工程外泌体的治疗潜力，通过可控和可量化的外部刺激，为其应用提供了广阔的前景。本研究旨在通过对间叶干细胞进行促炎预处理来提高外泌体的产生并增强其对 OA 的疗效，从而解决这些问题。研究人员从使用促炎因子 TNF-α 预处理的髌下脂肪垫（IPFP）-间充质干细胞的上清液中分离出外泌体，随后对其产生量进行了量化。在TNF-α预处理前后，通过高通量转录组测序分析、q-PCR和Western印迹分析评估了IPFP-间充质干细胞分泌外泌体的相关途径。此外，还将从TNF-α预处理的IPFP-间充质干细胞中提取的外泌体（IPFP-间充质干细胞-EXOsTNF-α）用于OA小鼠模型的关节内给药，并对关节病理学和步态改变进行了后续评估。通过蛋白质组分析确定了外泌体中参与维持软骨平衡的蛋白质的表达。与未经预处理的间充质干细胞相比，TNF-α的预处理能显著增强IPFP-间充质干细胞的外泌体分泌。其潜在机制是TNF-α预处理激活了IPFP-间充质干细胞的PI3K/AKT信号通路，导致自噬相关蛋白16 like 1（ATG16L1）水平上调，从而促进了外泌体的分泌。IPFP-间充质干细胞-EXOsTNF-α的关节内给药在改善OA小鼠关节病理变化方面表现出卓越的疗效。TNF-α的预处理增强了IPFP-间充质干细胞-EXOsTNF-α中低密度脂蛋白受体相关蛋白1（LRP1）水平的上调，从而发挥了软骨保护作用。TNF-α预处理是优化IPFP-间充质干细胞外泌体治疗OA疗效的一种有效且有前景的方法。
{"title":"Engineering exosomes derived from TNF-α preconditioned IPFP-MSCs enhance both yield and therapeutic efficacy for osteoarthritis","authors":"Jiangyi Wu, Jinhui Wu, Wei Xiang, Yunquan Gong, Daibo Feng, Shunzheng Fang, Yaran Wu, Zheng Liu, Yang Li, Ran Chen, Xiaoqi Zhang, Bingfei Li, Lifeng Chen, Runze Jin, Song Li, Bin Zhang, Tongyi Zhang, Lin Yin, Yizhao Zhou, Shu Huang, Ningning Liu, Hao Xu, Jiqin Lian, Yongqian Wang, Siru Zhou, Zhenhong Ni","doi":"10.1186/s12951-024-02795-9","DOIUrl":"https://doi.org/10.1186/s12951-024-02795-9","url":null,"abstract":"The pathogenesis of osteoarthritis (OA) involves the progressive degradation of articular cartilage. Exosomes derived from mesenchymal stem cells (MSC-EXOs) have been shown to mitigate joint pathological injury by attenuating cartilage destruction. Optimization the yield and therapeutic efficacy of exosomes derived from MSCs is crucial for promoting their clinical translation. The preconditioning of MSCs enhances the therapeutic potential of engineered exosomes, offering promising prospects for application by enabling controlled and quantifiable external stimulation. This study aims to address these issues by employing pro-inflammatory preconditioning of MSCs to enhance exosome production and augment their therapeutic efficacy for OA. The exosomes were isolated from the supernatant of infrapatellar fat pad (IPFP)-MSCs preconditioned with a pro-inflammatory factor, TNF-α, and their production was subsequently quantified. The exosome secretion-related pathways in IPFP-MSCs were evaluated through high-throughput transcriptome sequencing analysis, q-PCR and western blot analysis before and after TNF-α preconditioning. Furthermore, exosomes derived from TNF-α preconditioned IPFP-MSCs (IPFP-MSC-EXOsTNF−α) were administered intra-articularly in an OA mouse model, and subsequent evaluations were conducted to assess joint pathology and gait alterations. The expression of proteins involved in the maintenance of cartilage homeostasis within the exosomes was determined through proteomic analysis. The preconditioning with TNF-α significantly enhanced the exosome secretion of IPFP-MSCs compared to unpreconditioned MSCs. The potential mechanism involved the activation of the PI3K/AKT signaling pathway in IPFP-MSCs by TNF-α precondition, leading to an up-regulation of autophagy-related protein 16 like 1(ATG16L1) levels, which subsequently facilitated exosome secretion. The intra-articular administration of IPFP-MSC-EXOsTNF−α demonstrated superior efficacy in ameliorating pathological changes in the joints of OA mice. The preconditioning of TNF-α enhanced the up-regulation of low-density lipoprotein receptor-related protein 1 (LRP1) levels in IPFP-MSC-EXOsTNF−α, thereby exerting chondroprotective effects. TNF-α preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of IPFP-MSCs derived exosomes in the treatment of OA. ","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lipid nanoparticles (LNPs) are currently the most commonly used non-viral gene delivery system. Their physiochemical attributes, encompassing size, charge and surface modifications, significantly affect their behaviors both in vivo and in vitro. Nevertheless, the effects of these properties on the transfection and distribution of LNPs after intramuscular injection remain elusive. In this study, LNPs with varying sizes, lipid-based charges and PEGylated lipids were formulated to study their transfection and in vivo distribution. Luciferase mRNA (mLuc) was entraped in LNPs as a model nucleic acid molecule. Results indicated that smaller-sized LNPs and those with neutral potential presented superior transfection efficiency after intramuscular injection. Surprisingly, the sizes and charges did not exert a notable influence on the in vivo distribution of the LNPs. Furthermore, PEGylated lipids with shorter acyl chains contributed to enhanced transfection efficiency due to their superior cellular uptake and lysosomal escape capabilities. Notably, the mechanisms underlying cellular uptake differed among LNPs containing various types of PEGylated lipids, which was primarily attributed to the length of their acyl chain. Together, these insights underscore the pivotal role of nanoparticle characteristics and PEGylated lipids in the intramuscular route. This study not only fills crucial knowledge gaps but also provides significant directions for the effective delivery of mRNA via LNPs.
{"title":"Role of size, surface charge, and PEGylated lipids of lipid nanoparticles (LNPs) on intramuscular delivery of mRNA","authors":"Weiwen Kong, Yuning Wei, Zirong Dong, Wenjuan Liu, Jiaxin Zhao, Yan Huang, Jinlong Yang, Wei Wu, Haisheng He, Jianping Qi","doi":"10.1186/s12951-024-02812-x","DOIUrl":"https://doi.org/10.1186/s12951-024-02812-x","url":null,"abstract":"Lipid nanoparticles (LNPs) are currently the most commonly used non-viral gene delivery system. Their physiochemical attributes, encompassing size, charge and surface modifications, significantly affect their behaviors both in vivo and in vitro. Nevertheless, the effects of these properties on the transfection and distribution of LNPs after intramuscular injection remain elusive. In this study, LNPs with varying sizes, lipid-based charges and PEGylated lipids were formulated to study their transfection and in vivo distribution. Luciferase mRNA (mLuc) was entraped in LNPs as a model nucleic acid molecule. Results indicated that smaller-sized LNPs and those with neutral potential presented superior transfection efficiency after intramuscular injection. Surprisingly, the sizes and charges did not exert a notable influence on the in vivo distribution of the LNPs. Furthermore, PEGylated lipids with shorter acyl chains contributed to enhanced transfection efficiency due to their superior cellular uptake and lysosomal escape capabilities. Notably, the mechanisms underlying cellular uptake differed among LNPs containing various types of PEGylated lipids, which was primarily attributed to the length of their acyl chain. Together, these insights underscore the pivotal role of nanoparticle characteristics and PEGylated lipids in the intramuscular route. This study not only fills crucial knowledge gaps but also provides significant directions for the effective delivery of mRNA via LNPs. ","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1186/s12951-024-02796-8
Xina Yu, Jie Wang, Tiantian Wang, Shanshan Song, Hongna Su, Hui Huang, Pei Luo
Myocardial infarction (MI) is the main contributor to most cardiovascular diseases (CVDs), and the available post-treatment clinical therapeutic options are limited. The development of nanoscale drug delivery systems carrying natural small molecules provides biotherapies that could potentially offer new treatments for reactive oxygen species (ROS)-induced damage in MI. Considering the stability and reduced toxicity of gold-phenolic core-shell nanoparticles, this study aims to develop ellagic acid-functionalized gold nanoparticles (EA-AuNPs) to overcome these limitations. We have successfully synthesized EA-AuNPs with enhanced biocompatibility and bioactivity. These core-shell gold nanoparticles exhibit excellent ROS-scavenging activity and high dispersion. The results from a label-free imaging method on optically transparent zebrafish larvae models and micro-CT imaging in mice indicated that EA-AuNPs enable a favorable excretion-based metabolism without overburdening other organs. EA-AuNPs were subsequently applied in cellular oxidative stress models and MI mouse models. We found that they effectively inhibit the expression of apoptosis-related proteins and the elevation of cardiac enzyme activities, thereby ameliorating oxidative stress injuries in MI mice. Further investigations of oxylipin profiles indicated that EA-AuNPs might alleviate myocardial injury by inhibiting ROS-induced oxylipin level alterations, restoring the perturbed anti-inflammatory oxylipins. These findings collectively emphasized the protective role of EA-AuNPs in myocardial injury, which contributes to the development of innovative gold-phenolic nanoparticles and further advances their potential medical applications.
{"title":"Ellagic acid-enhanced biocompatibility and bioactivity in multilayer core-shell gold nanoparticles for ameliorating myocardial infarction injury","authors":"Xina Yu, Jie Wang, Tiantian Wang, Shanshan Song, Hongna Su, Hui Huang, Pei Luo","doi":"10.1186/s12951-024-02796-8","DOIUrl":"https://doi.org/10.1186/s12951-024-02796-8","url":null,"abstract":"Myocardial infarction (MI) is the main contributor to most cardiovascular diseases (CVDs), and the available post-treatment clinical therapeutic options are limited. The development of nanoscale drug delivery systems carrying natural small molecules provides biotherapies that could potentially offer new treatments for reactive oxygen species (ROS)-induced damage in MI. Considering the stability and reduced toxicity of gold-phenolic core-shell nanoparticles, this study aims to develop ellagic acid-functionalized gold nanoparticles (EA-AuNPs) to overcome these limitations. We have successfully synthesized EA-AuNPs with enhanced biocompatibility and bioactivity. These core-shell gold nanoparticles exhibit excellent ROS-scavenging activity and high dispersion. The results from a label-free imaging method on optically transparent zebrafish larvae models and micro-CT imaging in mice indicated that EA-AuNPs enable a favorable excretion-based metabolism without overburdening other organs. EA-AuNPs were subsequently applied in cellular oxidative stress models and MI mouse models. We found that they effectively inhibit the expression of apoptosis-related proteins and the elevation of cardiac enzyme activities, thereby ameliorating oxidative stress injuries in MI mice. Further investigations of oxylipin profiles indicated that EA-AuNPs might alleviate myocardial injury by inhibiting ROS-induced oxylipin level alterations, restoring the perturbed anti-inflammatory oxylipins. These findings collectively emphasized the protective role of EA-AuNPs in myocardial injury, which contributes to the development of innovative gold-phenolic nanoparticles and further advances their potential medical applications. ","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1186/s12951-024-02746-4
Emma M. McErlean, Helen O. McCarthy
Natural Killer (NK) cells are exciting candidates for cancer immunotherapy with potent innate cytotoxicity and distinct advantages over T cells for Chimeric Antigen Receptor (CAR) therapy. Concerns regarding the safety, cost, and scalability of viral vectors has ignited research into non-viral alternatives for gene delivery. This review comprehensively analyses recent advancements and challenges with non-viral genetic modification of NK cells for allogeneic CAR-NK therapies. Non-viral alternatives including electroporation and multifunctional nanoparticles are interrogated with respect to CAR expression and translational responses. Crucially, the link between NK cell biology and design of drug delivery technologies are made, which is essential for development of future non-viral approaches. This review provides valuable insights into the current state of non-viral CAR-NK cell engineering, aimed at realising the full potential of NK cell-based immunotherapies. Non-viral production of “off-the-shelf” CAR-NK cells. 1. NK cells may be purified from donor blood, differentiated from stem cells or produced from immortalised cell lines in the lab. 2. NK-specific CAR design modified from CAR-T designs to include NK transmembrane domains (NKG2D, NKp44), co-stimulatory receptors (e.g., DAP10, 2B4) and NK cell receptors (NKG2D). 3. Non-viral genetic modification of NK cells can include delivery of CAR construct via DNA or mRNA, and knock-in/out of specific genes using gene editing tools (e.g., CRISPR Cas9, transposons). This requires a gene delivery method which may include electroporation, lipid and multifunctional nanoparticles and cell penetrating peptides. The resultant CAR-NK cells are then expanded in vitro and may be delivered as an "off-the-shelf" product to treat multiple patients.
自然杀伤（NK）细胞是癌症免疫疗法中令人兴奋的候选细胞，具有强大的先天细胞毒性，在嵌合抗原受体（CAR）疗法中与 T 细胞相比具有明显优势。人们对病毒载体的安全性、成本和可扩展性的担忧点燃了对基因递送非病毒替代品的研究。本综述全面分析了用于异体 CAR-NK 疗法的 NK 细胞非病毒基因改造的最新进展和挑战。非病毒替代方法包括电穿孔和多功能纳米粒子，它们在 CAR 表达和转化反应方面均有研究。最重要的是，该综述将 NK 细胞生物学与给药技术设计联系起来，这对未来非病毒疗法的开发至关重要。这篇综述为非病毒 CAR-NK 细胞工程的现状提供了宝贵的见解，旨在充分发挥基于 NK 细胞的免疫疗法的潜力。非病毒生产 "现成的 "CAR-NK 细胞。1.NK 细胞可以从供体血液中纯化、从干细胞中分化或在实验室中从永生细胞系中产生。2.根据 CAR-T 设计修改 NK 特异性 CAR 设计，以包括 NK 跨膜结构域（NKG2D、NKp44）、共刺激受体（如 DAP10、2B4）和 NK 细胞受体（NKG2D）。3.3. NK 细胞的非病毒基因改造可包括通过 DNA 或 mRNA 运送 CAR 构建物，以及使用基因编辑工具（如 CRISPR Cas9、转座子）敲入/敲出特定基因。这需要一种基因递送方法，其中可能包括电穿孔、脂质和多功能纳米颗粒以及细胞穿透肽。由此产生的 CAR-NK 细胞随后在体外扩增，并可作为 "现成 "产品用于治疗多名患者。
{"title":"Non-viral approaches in CAR-NK cell engineering: connecting natural killer cell biology and gene delivery","authors":"Emma M. McErlean, Helen O. McCarthy","doi":"10.1186/s12951-024-02746-4","DOIUrl":"https://doi.org/10.1186/s12951-024-02746-4","url":null,"abstract":"Natural Killer (NK) cells are exciting candidates for cancer immunotherapy with potent innate cytotoxicity and distinct advantages over T cells for Chimeric Antigen Receptor (CAR) therapy. Concerns regarding the safety, cost, and scalability of viral vectors has ignited research into non-viral alternatives for gene delivery. This review comprehensively analyses recent advancements and challenges with non-viral genetic modification of NK cells for allogeneic CAR-NK therapies. Non-viral alternatives including electroporation and multifunctional nanoparticles are interrogated with respect to CAR expression and translational responses. Crucially, the link between NK cell biology and design of drug delivery technologies are made, which is essential for development of future non-viral approaches. This review provides valuable insights into the current state of non-viral CAR-NK cell engineering, aimed at realising the full potential of NK cell-based immunotherapies. Non-viral production of “off-the-shelf” CAR-NK cells. 1. NK cells may be purified from donor blood, differentiated from stem cells or produced from immortalised cell lines in the lab. 2. NK-specific CAR design modified from CAR-T designs to include NK transmembrane domains (NKG2D, NKp44), co-stimulatory receptors (e.g., DAP10, 2B4) and NK cell receptors (NKG2D). 3. Non-viral genetic modification of NK cells can include delivery of CAR construct via DNA or mRNA, and knock-in/out of specific genes using gene editing tools (e.g., CRISPR Cas9, transposons). This requires a gene delivery method which may include electroporation, lipid and multifunctional nanoparticles and cell penetrating peptides. The resultant CAR-NK cells are then expanded in vitro and may be delivered as an \"off-the-shelf\" product to treat multiple patients. ","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.2,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8+ T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment.
{"title":"Rationally designed catalytic nanoplatform for enhanced chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment","authors":"Daxi Sun, Liting Yu, Gang Wang, Yuxue Xu, Peng Wang, Ningning Wang, Zhengyan Wu, Guilong Zhang, Jia Zhang, Yunjiao Zhang, Geng Tian, Pengfei Wei","doi":"10.1186/s12951-024-02696-x","DOIUrl":"https://doi.org/10.1186/s12951-024-02696-x","url":null,"abstract":"Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8+ T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment. ","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142224952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1186/s12951-024-02828-3
Kun Li, Leilei Wu, Han Wang, Zi Fu, Jiani Gao, Xiucheng Liu, Yongfei Fan, Xichun Qin, Dalong Ni, Jing Wang, Dong Xie
Lung cancer, predominantly non-small cell lung cancer (NSCLC), remains a significant global health challenge, with limited therapeutic options for patients with KRAS-mutated tumors. Herein, a copper-based metal-organic framework (Cu-MOF) was applied as a novel cuproptosis-mediated nanoplatform for lung cancer therapy. Cu-MOF would disassemble and liberate copper ions under the acidic microenvironment of lysosomes of cancer cells, initiating a cascade of cellular events. The released copper ions catalyzes the Fenton reaction, generating hydroxyl radicals that induce oxidative damage, leading to cytoskeletal disruption and activation of caspase-3, ultimately triggering apoptosis. Simultaneously, with the mediation of the key regulatory factor FDX1, we found that the copper ions binding to the mitochondrial protein DLAT could result in the loss of iron-sulfur cluster proteins and aggregation of lipoylated proteins, which culminated in proteotoxic stress-induced cuproptosis. The pronounced anti-tumor effects of Cu-MOF with apoptosis and cuproptosis were confirmed both in vitro and in vivo experiments. Such dual induction of apoptosis and cuproptosis by Cu-MOF presents a promising therapeutic strategy for NSCLC, particularly for KRAS-mutated tumors, and expands potential applications of Cu-based nanomateirals for other cancers.
{"title":"Apoptosis and cuproptosis Co-activated Copper-based metal-organic frameworks for cancer therapy.","authors":"Kun Li, Leilei Wu, Han Wang, Zi Fu, Jiani Gao, Xiucheng Liu, Yongfei Fan, Xichun Qin, Dalong Ni, Jing Wang, Dong Xie","doi":"10.1186/s12951-024-02828-3","DOIUrl":"10.1186/s12951-024-02828-3","url":null,"abstract":"<p><p>Lung cancer, predominantly non-small cell lung cancer (NSCLC), remains a significant global health challenge, with limited therapeutic options for patients with KRAS-mutated tumors. Herein, a copper-based metal-organic framework (Cu-MOF) was applied as a novel cuproptosis-mediated nanoplatform for lung cancer therapy. Cu-MOF would disassemble and liberate copper ions under the acidic microenvironment of lysosomes of cancer cells, initiating a cascade of cellular events. The released copper ions catalyzes the Fenton reaction, generating hydroxyl radicals that induce oxidative damage, leading to cytoskeletal disruption and activation of caspase-3, ultimately triggering apoptosis. Simultaneously, with the mediation of the key regulatory factor FDX1, we found that the copper ions binding to the mitochondrial protein DLAT could result in the loss of iron-sulfur cluster proteins and aggregation of lipoylated proteins, which culminated in proteotoxic stress-induced cuproptosis. The pronounced anti-tumor effects of Cu-MOF with apoptosis and cuproptosis were confirmed both in vitro and in vivo experiments. Such dual induction of apoptosis and cuproptosis by Cu-MOF presents a promising therapeutic strategy for NSCLC, particularly for KRAS-mutated tumors, and expands potential applications of Cu-based nanomateirals for other cancers.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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