Pub Date : 2024-10-18DOI: 10.1186/s12951-024-02866-x
Yong Li, Xinyi Zhu, Wei Xiong, Qingyu Zhao, Youdong Zhou, Yujia Guo, Baohui Liu, Mingchang Li, Qianxue Chen, Xiaobing Jiang, Yangzhi Qi, Qingsong Ye, Gang Deng
Background: Subarachnoid hemorrhage (SAH) is a life -threatening cerebrovascular disease, where early brain injury (EBI) stands as a primary contributor to mortality and unfavorable patient outcomes. Neuronal ferroptosis emerges as a key pathological mechanism underlying EBI in SAH. Targeting ferroptosis for therapeutic intervention in SAH holds significant promise as a treatment strategy.
Methods: SAH model was induced via intravascular puncture and quantitatively assessed the presence of neuronal ferroptosis in the early phase of SAH using FJC staining, Prussian blue staining, as well as malondialdehyde (MDA) and glutathione (GSH) measurements. Hyaluronic acid-coated ursolic acid nanoparticles (HA-PEG-UA NPs) were prepared using the solvent evaporation method. We investigated the in vivo distribution of HA-PEG-UA NPs in SAH model through IVIS and fluorescence observation, and examined their impact on short-term neurological function and cortical neurological injury. Finally, we assessed the effect of UA on the Nrf-2/SLC7A11/GPX4 axis via Western Blot analysis.
Results: We successfully developed self-assembled UA NPs with hyaluronic acid to target the increased CD44 expression in the SAH-afflicted brain. The resulting HA-PEG-UA NPs facilitated delivery and enrichment of UA within the SAH-affected region. The targeted delivery of UA to the SAH region can effectively inhibit neuronal ferroptosis, improve neurological deficits, and prognosis in mice. Its mechanism of action is associated with the activation of the Nrf-2/SLC7A11/GPX4 signaling pathway.
Conclusions: Brain-targeted HA-PEG-UA NPs was successfully developed and hold the potential to enhance SAH prognosis by limiting neuronal ferroptosis via modulation of the Nrf-2/SLC7A11/GPX4 signal.
背景:蛛网膜下腔出血(SAH)是一种危及生命的脑血管疾病,早期脑损伤(EBI)是导致患者死亡和不良预后的主要因素。神经元铁变态反应是导致 SAH 早期脑损伤的关键病理机制。针对嗜铁细胞增多症干预SAH的治疗策略前景广阔:方法:通过血管内穿刺诱导 SAH 模型,并使用 FJC 染色、普鲁士蓝染色以及丙二醛(MDA)和谷胱甘肽(GSH)测定定量评估 SAH 早期神经元铁突变的存在。我们采用溶剂蒸发法制备了透明质酸包覆熊果酸的纳米颗粒(HA-PEG-UA NPs)。我们通过IVIS和荧光观察研究了HA-PEG-UA NPs在SAH模型中的体内分布,并考察了它们对短期神经功能和皮层神经损伤的影响。最后,我们通过 Western Blot 分析评估了 UA 对 Nrf-2/SLC7A11/GPX4 轴的影响:结果:我们成功开发出了与透明质酸自组装的 UA NPs,以针对 SAH 患者大脑中 CD44 表达的增加。由此产生的HA-PEG-UA NPs促进了UA在SAH影响区域内的递送和富集。向SAH区域靶向递送UA能有效抑制小鼠神经元铁凋亡,改善神经功能缺损和预后。其作用机制与激活Nrf-2/SLC7A11/GPX4信号通路有关:脑靶向HA-PEG-UA NPs研制成功,有望通过调节Nrf-2/SLC7A11/GPX4信号限制神经元铁凋亡,从而改善SAH预后。
{"title":"Brain-targeted ursolic acid nanoparticles for anti-ferroptosis therapy in subarachnoid hemorrhage.","authors":"Yong Li, Xinyi Zhu, Wei Xiong, Qingyu Zhao, Youdong Zhou, Yujia Guo, Baohui Liu, Mingchang Li, Qianxue Chen, Xiaobing Jiang, Yangzhi Qi, Qingsong Ye, Gang Deng","doi":"10.1186/s12951-024-02866-x","DOIUrl":"10.1186/s12951-024-02866-x","url":null,"abstract":"<p><strong>Background: </strong>Subarachnoid hemorrhage (SAH) is a life -threatening cerebrovascular disease, where early brain injury (EBI) stands as a primary contributor to mortality and unfavorable patient outcomes. Neuronal ferroptosis emerges as a key pathological mechanism underlying EBI in SAH. Targeting ferroptosis for therapeutic intervention in SAH holds significant promise as a treatment strategy.</p><p><strong>Methods: </strong>SAH model was induced via intravascular puncture and quantitatively assessed the presence of neuronal ferroptosis in the early phase of SAH using FJC staining, Prussian blue staining, as well as malondialdehyde (MDA) and glutathione (GSH) measurements. Hyaluronic acid-coated ursolic acid nanoparticles (HA-PEG-UA NPs) were prepared using the solvent evaporation method. We investigated the in vivo distribution of HA-PEG-UA NPs in SAH model through IVIS and fluorescence observation, and examined their impact on short-term neurological function and cortical neurological injury. Finally, we assessed the effect of UA on the Nrf-2/SLC7A11/GPX4 axis via Western Blot analysis.</p><p><strong>Results: </strong>We successfully developed self-assembled UA NPs with hyaluronic acid to target the increased CD44 expression in the SAH-afflicted brain. The resulting HA-PEG-UA NPs facilitated delivery and enrichment of UA within the SAH-affected region. The targeted delivery of UA to the SAH region can effectively inhibit neuronal ferroptosis, improve neurological deficits, and prognosis in mice. Its mechanism of action is associated with the activation of the Nrf-2/SLC7A11/GPX4 signaling pathway.</p><p><strong>Conclusions: </strong>Brain-targeted HA-PEG-UA NPs was successfully developed and hold the potential to enhance SAH prognosis by limiting neuronal ferroptosis via modulation of the Nrf-2/SLC7A11/GPX4 signal.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11490124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467816","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}
Pub Date : 2024-10-16DOI: 10.1186/s12951-024-02904-8
Ming Yang, Kui Gu, Qiang Xu, Renqiao Wen, Jinpeng Li, Changyu Zhou, Yu Zhao, Miwan Shi, Yuan Weng, Boyan Guo, Changwei Lei, Yong Sun, Hongning Wang
Salmonella Enteritidis is a major foodborne pathogen throughout the world and the increase in antibiotic resistance of Salmonella poses a significant threat to public safety. Natural nanobodies exhibit high affinity, thermal stability, ease of production, and notably higher diversity, making them widely applicable for the treatment of viral and bacterial infections. Recombinant expression using Lactococcus lactis leverages both acid resistance and mucosal colonization properties of these bacteria, allowing the effective expression of exogenous proteins for therapeutic effects. In this study, nine specific nanobodies against the flagellar protein FliC were identified and expressed. In vitro experiments demonstrated that FliC-Nb-76 effectively inhibited the motility of S. Enteritidis and inhibited its adhesion to and invasion of HIEC-6, RAW264.7, and chicken intestinal epithelial cells. Additionally, a recombinant L. lactis strain secreting the nanobody, L. lactis-Nb76, was obtained. Animal experiments confirmed that it could significantly reduce the mortality rates of chickens infected with S. Enteritidis, together with alleviating the inflammatory response caused by the pathogen. These results provide a novel strategy for the treatment of antibiotic-resistant S. Enteritidis infection in the intestinal tract.
肠炎沙门氏菌是全球主要的食源性病原体,沙门氏菌抗生素耐药性的增加对公共安全构成了重大威胁。天然纳米抗体具有高亲和性、热稳定性、易生产性和显著的高多样性,因此可广泛用于治疗病毒和细菌感染。利用乳酸乳球菌进行重组表达,可充分利用这些细菌的耐酸性和粘膜定植特性,从而有效表达外源蛋白质,达到治疗效果。本研究鉴定并表达了九种针对鞭毛蛋白 FliC 的特异性纳米抗体。体外实验表明,FliC-Nb-76 能有效抑制肠炎双球菌的运动,并抑制其粘附和侵入 HIEC-6、RAW264.7 和鸡肠道上皮细胞。此外,还获得了能分泌纳米抗体的重组乳杆菌菌株 L. lactis-Nb76。动物实验证实,它能显著降低感染肠炎双球菌的鸡的死亡率,同时减轻病原体引起的炎症反应。这些结果为治疗肠道中的抗生素耐药肠炎球菌感染提供了一种新策略。
{"title":"Recombinant Lactococcus lactis secreting FliC protein nanobodies for resistance against Salmonella enteritidis invasion in the intestinal tract.","authors":"Ming Yang, Kui Gu, Qiang Xu, Renqiao Wen, Jinpeng Li, Changyu Zhou, Yu Zhao, Miwan Shi, Yuan Weng, Boyan Guo, Changwei Lei, Yong Sun, Hongning Wang","doi":"10.1186/s12951-024-02904-8","DOIUrl":"https://doi.org/10.1186/s12951-024-02904-8","url":null,"abstract":"<p><p>Salmonella Enteritidis is a major foodborne pathogen throughout the world and the increase in antibiotic resistance of Salmonella poses a significant threat to public safety. Natural nanobodies exhibit high affinity, thermal stability, ease of production, and notably higher diversity, making them widely applicable for the treatment of viral and bacterial infections. Recombinant expression using Lactococcus lactis leverages both acid resistance and mucosal colonization properties of these bacteria, allowing the effective expression of exogenous proteins for therapeutic effects. In this study, nine specific nanobodies against the flagellar protein FliC were identified and expressed. In vitro experiments demonstrated that FliC-Nb-76 effectively inhibited the motility of S. Enteritidis and inhibited its adhesion to and invasion of HIEC-6, RAW264.7, and chicken intestinal epithelial cells. Additionally, a recombinant L. lactis strain secreting the nanobody, L. lactis-Nb76, was obtained. Animal experiments confirmed that it could significantly reduce the mortality rates of chickens infected with S. Enteritidis, together with alleviating the inflammatory response caused by the pathogen. These results provide a novel strategy for the treatment of antibiotic-resistant S. Enteritidis infection in the intestinal tract.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467836","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}
Photothermal therapy (PTT) is a promising non-invasive treatment that has shown great potential in eliminating tumors. It not only induces apoptosis of cancer cells but also triggers immunogenic cell death (ICD) which could activate the immune system against cancer. However, the immunosuppressive tumor microenvironment (TIME) poses a challenge to triggering strong immune responses with a single treatment, thus limiting the therapeutic effect of cancer immunotherapy. In this study, dual-targeted nano delivery system (GOx@FeNPs) combined with αPD-L1 immune checkpoint blocker could inhibit colorectal cancer (CRC) progression by mediating PTT, ferroptosis and anti-tumor immune response. Briefly, specific tumor delivery was achieved by the cyclic arginine glycyl aspartate (cRGD) peptide and anisamide (AA) in GOx@FeNPs which not only had a good photothermal effect to realize PTT and induce ICD, but also could deplete glutathione (GSH) and catalyze the production of reactive oxygen species (ROS) from endogenous H2O2. All these accelerated the Fenton reaction and augmented the process of PTT-induced ICD. Thus, a large amount of tumor specific antigen was released to stimulate the maturation of dendritic cells (DCs) in lymph nodes and enhance the infiltration of CD8+ T cells in tumor. At the same time, the combination with αPD-L1 has favorable synergistic effectiveness against CRC with tumor inhibition rate over 90%. Furthermore, GOx@FeNPs had good magnetic resonance imaging (MRI) capability under T2-weighting owing to the presence of Fe3+, which is favorable for integrated diagnosis and treatment systems of CRC. By constructing a dual-targeted GOx@FeNPs nanoplatform, PTT synergistically combined with ferroptosis was realized to improve the immunotherapeutic effect, providing a new approach for CRC immunotherapy.
光热疗法(PTT)是一种前景广阔的非侵入性疗法,在消除肿瘤方面显示出巨大的潜力。它不仅能诱导癌细胞凋亡,还能引发免疫性细胞死亡(ICD),从而激活免疫系统对抗癌症。然而,免疫抑制性肿瘤微环境(TIME)对单次治疗引发强烈的免疫反应构成了挑战,从而限制了癌症免疫疗法的治疗效果。在这项研究中,双靶向纳米递送系统(GOx@FeNPs)与αPD-L1免疫检查点阻断剂相结合,可通过介导PTT、铁突变和抗肿瘤免疫反应抑制结直肠癌(CRC)的进展。简而言之,GOx@FeNPs中的环精氨酸甘氨酰天冬氨酸(cRGD)肽和茴香酰胺(AA)实现了特异性肿瘤递送,不仅具有良好的光热效应,可实现PTT和诱导ICD,还能消耗谷胱甘肽(GSH),催化内源性H2O2产生活性氧(ROS)。所有这些都加速了芬顿反应,增强了 PTT 诱导 ICD 的过程。因此,大量肿瘤特异性抗原被释放出来,刺激淋巴结中树突状细胞(DCs)的成熟,并增强 CD8+ T 细胞对肿瘤的浸润。同时,与αPD-L1联用对CRC具有良好的协同作用,抑瘤率超过90%。此外,由于Fe3+的存在,GOx@FeNPs在T2加权下具有良好的磁共振成像(MRI)能力,有利于CRC的综合诊断和治疗系统。通过构建双靶向GOx@FeNPs纳米平台,实现了PTT与铁突变的协同作用,提高了免疫治疗效果,为CRC免疫治疗提供了一种新方法。
{"title":"Photothermal Fe<sub>3</sub>O<sub>4</sub> nanoparticles induced immunogenic ferroptosis for synergistic colorectal cancer therapy.","authors":"Yue Li, Jia Chen, Qi Xia, Jing Shang, Yujie He, Zhi Li, Yingying Chen, Feng Gao, Xi Yu, Zeting Yuan, Peihao Yin","doi":"10.1186/s12951-024-02909-3","DOIUrl":"https://doi.org/10.1186/s12951-024-02909-3","url":null,"abstract":"<p><p>Photothermal therapy (PTT) is a promising non-invasive treatment that has shown great potential in eliminating tumors. It not only induces apoptosis of cancer cells but also triggers immunogenic cell death (ICD) which could activate the immune system against cancer. However, the immunosuppressive tumor microenvironment (TIME) poses a challenge to triggering strong immune responses with a single treatment, thus limiting the therapeutic effect of cancer immunotherapy. In this study, dual-targeted nano delivery system (GOx@FeNPs) combined with αPD-L1 immune checkpoint blocker could inhibit colorectal cancer (CRC) progression by mediating PTT, ferroptosis and anti-tumor immune response. Briefly, specific tumor delivery was achieved by the cyclic arginine glycyl aspartate (cRGD) peptide and anisamide (AA) in GOx@FeNPs which not only had a good photothermal effect to realize PTT and induce ICD, but also could deplete glutathione (GSH) and catalyze the production of reactive oxygen species (ROS) from endogenous H<sub>2</sub>O<sub>2</sub>. All these accelerated the Fenton reaction and augmented the process of PTT-induced ICD. Thus, a large amount of tumor specific antigen was released to stimulate the maturation of dendritic cells (DCs) in lymph nodes and enhance the infiltration of CD8<sup>+</sup> T cells in tumor. At the same time, the combination with αPD-L1 has favorable synergistic effectiveness against CRC with tumor inhibition rate over 90%. Furthermore, GOx@FeNPs had good magnetic resonance imaging (MRI) capability under T2-weighting owing to the presence of Fe<sup>3+</sup>, which is favorable for integrated diagnosis and treatment systems of CRC. By constructing a dual-targeted GOx@FeNPs nanoplatform, PTT synergistically combined with ferroptosis was realized to improve the immunotherapeutic effect, providing a new approach for CRC immunotherapy.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467835","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}
Background: Exosomes (EXO) play crucial roles in intercellular communication and glioma microenvironment modulation. Tumor-associated macrophages are more likely to become M2-like type macrophages in the immunosuppressive microenvironment. Here, we aimed to investigate the effects and molecular mechanisms of hypoxic glioma-derived exosomes mediated M2-like macrophage polarization.
Methods: Highly expressed miRNAs in exosomes derived from glioma cells cultured under hypoxia condition compared to normoxic condition were identified through microRNA sequencing. The polarization status of macrophages was determined using qRT-PCR, Western blotting, flow cytometry, and immunohistochemistry. By using RNA-seq, we aimed to identify the downstream target genes regulated by miR-25-3p in macrophages and investigate the mechanistic pathways through which it exerts its effects. The proliferation and migration capabilities of glioma cells were assessed through EdU, Transwell assays, and in vivo experiments.
Results: We found that miR-25-3p was upregulated in the exosomes derived from hypoxic glioma cells and can be transferred to the macrophage. In macrophages, miR-25-3p downregulates the expression of PHLPP2, thereby activating the PI3K-AKT-mTOR signaling pathway, ultimately leading to macrophage M2 polarization. As part of a feedback loop, M2-polarized macrophages can, in turn, promote malignant glioma progression.
Conclusion: Our study reveals that miR-25-3p from hypoxic glioma cells is delivered to macrophages via exosomes as a mediator, promoting M2 polarization of macrophages through the miR-25-3p/PHLPP2/PI3K-AKT signaling pathway. This study suggests that targeted interventions to modulate miR-25-3p expression, transmission, or inhibition of PI3K-AKT pathway activation can disrupt the immune-suppressive microenvironment, providing a novel approach for immunotherapy in gliomas.
{"title":"Hypoxic glioma-derived exosomal miR-25-3p promotes macrophage M2 polarization by activating the PI3K-AKT-mTOR signaling pathway.","authors":"Zhiwei Xue, Junzhi Liu, Wenchen Xing, Feiyu Mu, Yanzhao Wu, Jiangli Zhao, Xuchen Liu, Donghai Wang, Jian Wang, Xingang Li, Jiwei Wang, Bin Huang","doi":"10.1186/s12951-024-02888-5","DOIUrl":"https://doi.org/10.1186/s12951-024-02888-5","url":null,"abstract":"<p><strong>Background: </strong>Exosomes (EXO) play crucial roles in intercellular communication and glioma microenvironment modulation. Tumor-associated macrophages are more likely to become M2-like type macrophages in the immunosuppressive microenvironment. Here, we aimed to investigate the effects and molecular mechanisms of hypoxic glioma-derived exosomes mediated M2-like macrophage polarization.</p><p><strong>Methods: </strong>Highly expressed miRNAs in exosomes derived from glioma cells cultured under hypoxia condition compared to normoxic condition were identified through microRNA sequencing. The polarization status of macrophages was determined using qRT-PCR, Western blotting, flow cytometry, and immunohistochemistry. By using RNA-seq, we aimed to identify the downstream target genes regulated by miR-25-3p in macrophages and investigate the mechanistic pathways through which it exerts its effects. The proliferation and migration capabilities of glioma cells were assessed through EdU, Transwell assays, and in vivo experiments.</p><p><strong>Results: </strong>We found that miR-25-3p was upregulated in the exosomes derived from hypoxic glioma cells and can be transferred to the macrophage. In macrophages, miR-25-3p downregulates the expression of PHLPP2, thereby activating the PI3K-AKT-mTOR signaling pathway, ultimately leading to macrophage M2 polarization. As part of a feedback loop, M2-polarized macrophages can, in turn, promote malignant glioma progression.</p><p><strong>Conclusion: </strong>Our study reveals that miR-25-3p from hypoxic glioma cells is delivered to macrophages via exosomes as a mediator, promoting M2 polarization of macrophages through the miR-25-3p/PHLPP2/PI3K-AKT signaling pathway. This study suggests that targeted interventions to modulate miR-25-3p expression, transmission, or inhibition of PI3K-AKT pathway activation can disrupt the immune-suppressive microenvironment, providing a novel approach for immunotherapy in gliomas.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467825","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}
Pub Date : 2024-10-16DOI: 10.1186/s12951-024-02854-1
Dan He, ZhiHui Li, Min Wang, Dejun Kong, Wenyan Guo, Xuliang Xia, Dong Li, Daijun Zhou
In patients with abdominal or pelvic tumors, radiotherapy can result in radiation-induced intestinal injury (RIII), a potentially severe complication for which there are few effective therapeutic options. Sitagliptin (SI) is an oral hypoglycemic drug that exhibits antiapoptotic, antioxidant, and anti-inflammatory activity, but how it influences RIII-associated outcomes has yet to be established. In this study, a pH-responsive metal-organic framework-based nanoparticle platform was developed for the delivery of SI (SI@ZIF-8@MS NP). These NPs incorporated mPEG-b-PLLA (MS) as an agent capable of resisting the effects of gastric acid, and are capable of releasing Zn2+ ions. MS was able to effectively shield these SI@ZIF-8 NPs from rapid degradation when exposed to an acidic environment, enabling the subsequent release of SI and Zn2+ within the intestinal fluid. Notably, SI@ZIF-8@MS treatment was able to mitigate radiation-induced intestinal dysbiosis in these mice. restored radiation-induced changes in bacterial composition. In summary, these data demonstrate the ability of SI@ZIF-8@MS to protect against WAI-induced intestinal damage in mice, suggesting that these NPs represent a multimodal targeted therapy that can effectively be used in the prevention or treatment of RIII.
{"title":"Metal-organic-framework-based sitagliptin-release platform for multieffective radiation-induced intestinal injury targeting therapy and intestinal flora protective capabilities.","authors":"Dan He, ZhiHui Li, Min Wang, Dejun Kong, Wenyan Guo, Xuliang Xia, Dong Li, Daijun Zhou","doi":"10.1186/s12951-024-02854-1","DOIUrl":"https://doi.org/10.1186/s12951-024-02854-1","url":null,"abstract":"<p><p>In patients with abdominal or pelvic tumors, radiotherapy can result in radiation-induced intestinal injury (RIII), a potentially severe complication for which there are few effective therapeutic options. Sitagliptin (SI) is an oral hypoglycemic drug that exhibits antiapoptotic, antioxidant, and anti-inflammatory activity, but how it influences RIII-associated outcomes has yet to be established. In this study, a pH-responsive metal-organic framework-based nanoparticle platform was developed for the delivery of SI (SI@ZIF-8@MS NP). These NPs incorporated mPEG-b-PLLA (MS) as an agent capable of resisting the effects of gastric acid, and are capable of releasing Zn<sup>2+</sup> ions. MS was able to effectively shield these SI@ZIF-8 NPs from rapid degradation when exposed to an acidic environment, enabling the subsequent release of SI and Zn<sup>2+</sup> within the intestinal fluid. Notably, SI@ZIF-8@MS treatment was able to mitigate radiation-induced intestinal dysbiosis in these mice. restored radiation-induced changes in bacterial composition. In summary, these data demonstrate the ability of SI@ZIF-8@MS to protect against WAI-induced intestinal damage in mice, suggesting that these NPs represent a multimodal targeted therapy that can effectively be used in the prevention or treatment of RIII.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467829","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}
Pub Date : 2024-10-16DOI: 10.1186/s12951-024-02902-w
Yeshen Zhang, Xinzhong Li, Yining Dai, Yuan Han, Xiaomin Wei, Guoquan Wei, Weikun Chen, Siyu Kong, Yu He, Haobin Liu, Ning Ma, Jianping Bin, Ning Tan, Pengcheng He, Yuanhui Liu
Neutrophil polarization contributes to inflammation and its resolution, but the role of neutrophil polarization in myocardial ischemia/reperfusion (I/R) injury remains unknown. Cardiomyocytes (CMs) participate in cardiac inflammation by secreting extracellular vesicles (EVs). Therefore, we investigated the role of neutrophil polarization in myocardial I/R injury and the mechanism by which CM-derived EVs regulated neutrophil polarization. In the present study, our data showed that N1 neutrophil polarization enlarged cardiac infarct size and exacerbated cardiac dysfunction at the early stage of myocardial I/R. Further, CM-EV-derived miR-9-5p was identified as a mediator inducing neutrophils to the N1 phenotype. Mechanistically, miR-9-5p directly suppressed SOCS5 and SIRT1 expression, resulting in activating JAK2/STAT3 and NF-κB signaling pathways in neutrophils. Importantly, we confirmed that serum EV-derived miR-9-5p levels were independently associated with cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. These findings suggest neutrophil polarization is a promising therapeutic target against myocardial I/R-induced inflammation and injury, and serum EV-derived miR-9-5p is a promising prognostic biomarker for cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.
中性粒细胞极化有助于炎症及其缓解,但中性粒细胞极化在心肌缺血/再灌注(I/R)损伤中的作用仍不清楚。心肌细胞(CMs)通过分泌细胞外囊泡(EVs)参与心脏炎症。因此,我们研究了中性粒细胞极化在心肌 I/R 损伤中的作用以及 CM 衍生的 EVs 调节中性粒细胞极化的机制。在本研究中,我们的数据显示,在心肌I/R早期,N1中性粒细胞极化扩大了心肌梗死面积并加剧了心脏功能障碍。此外,CM-EV 衍生的 miR-9-5p 被确定为诱导中性粒细胞形成 N1 表型的介质。从机制上讲,miR-9-5p 直接抑制了 SOCS5 和 SIRT1 的表达,从而激活了中性粒细胞中的 JAK2/STAT3 和 NF-κB 信号通路。重要的是,我们证实,在接受经皮冠状动脉介入治疗的 ST 段抬高型心肌梗死患者中,血清中 EV 衍生的 miR-9-5p 水平与心血管死亡率独立相关。这些研究结果表明,中性粒细胞极化是对抗心肌I/R诱导的炎症和损伤的一个有希望的治疗靶点,而血清EV衍生的miR-9-5p是接受经皮冠状动脉介入治疗的ST段抬高型心肌梗死患者心血管死亡率的一个有希望的预后生物标志物。
{"title":"Neutrophil N1 polarization induced by cardiomyocyte-derived extracellular vesicle miR-9-5p aggravates myocardial ischemia/reperfusion injury.","authors":"Yeshen Zhang, Xinzhong Li, Yining Dai, Yuan Han, Xiaomin Wei, Guoquan Wei, Weikun Chen, Siyu Kong, Yu He, Haobin Liu, Ning Ma, Jianping Bin, Ning Tan, Pengcheng He, Yuanhui Liu","doi":"10.1186/s12951-024-02902-w","DOIUrl":"https://doi.org/10.1186/s12951-024-02902-w","url":null,"abstract":"<p><p>Neutrophil polarization contributes to inflammation and its resolution, but the role of neutrophil polarization in myocardial ischemia/reperfusion (I/R) injury remains unknown. Cardiomyocytes (CMs) participate in cardiac inflammation by secreting extracellular vesicles (EVs). Therefore, we investigated the role of neutrophil polarization in myocardial I/R injury and the mechanism by which CM-derived EVs regulated neutrophil polarization. In the present study, our data showed that N1 neutrophil polarization enlarged cardiac infarct size and exacerbated cardiac dysfunction at the early stage of myocardial I/R. Further, CM-EV-derived miR-9-5p was identified as a mediator inducing neutrophils to the N1 phenotype. Mechanistically, miR-9-5p directly suppressed SOCS5 and SIRT1 expression, resulting in activating JAK2/STAT3 and NF-κB signaling pathways in neutrophils. Importantly, we confirmed that serum EV-derived miR-9-5p levels were independently associated with cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. These findings suggest neutrophil polarization is a promising therapeutic target against myocardial I/R-induced inflammation and injury, and serum EV-derived miR-9-5p is a promising prognostic biomarker for cardiovascular mortality in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467832","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}
Pub Date : 2024-10-16DOI: 10.1186/s12951-024-02926-2
Yindi Xiong, Taiyu Shen, Peng Lou, Jingyue Yang, John P Kastelic, Jingping Liu, Chuang Xu, Bo Han, Jian Gao
Bovine mastitis is an infectious disease that causes substantial economic losses to the dairy industry worldwide. Current antibiotic therapy faces issues of antibiotic misuse and antimicrobial resistance, which has aroused concerns for both veterinary and human medicine. Thus, this study explored the potential of Colo EVs (bovine colostrum-derived extracellular vesicles) to address mastitis. Using LPS-induced murine mammary epithelial cells (HC11), mouse monocyte macrophages (RAW 264.7), and a murine mastitis model with BALB/C mice, we evaluated the safety and efficacy of Colo EVs, in vivo and in vitro. Colo EVs had favorable biosafety profiles, promoting cell proliferation and migration without inducing pathological changes after injection into murine mammary glands. In LPS-induced murine mastitis, Colo EVs significantly reduced inflammation, improved inflammatory scores, and preserved tight junction proteins while protecting milk production. Additionally, in vitro experiments demonstrated that Colo EVs downregulated inflammatory cytokine expression, reduced inflammatory markers, and attenuated NF-κB pathway activation. In summary, we inferred that Colo EVs have promise as a therapeutic approach for mastitis treatment, owing to their anti-inflammatory properties, potentially mediated through the NF-κB signaling pathway modulation.
{"title":"Colostrum-derived extracellular vesicles: potential multifunctional nanomedicine for alleviating mastitis.","authors":"Yindi Xiong, Taiyu Shen, Peng Lou, Jingyue Yang, John P Kastelic, Jingping Liu, Chuang Xu, Bo Han, Jian Gao","doi":"10.1186/s12951-024-02926-2","DOIUrl":"https://doi.org/10.1186/s12951-024-02926-2","url":null,"abstract":"<p><p>Bovine mastitis is an infectious disease that causes substantial economic losses to the dairy industry worldwide. Current antibiotic therapy faces issues of antibiotic misuse and antimicrobial resistance, which has aroused concerns for both veterinary and human medicine. Thus, this study explored the potential of Colo EVs (bovine colostrum-derived extracellular vesicles) to address mastitis. Using LPS-induced murine mammary epithelial cells (HC11), mouse monocyte macrophages (RAW 264.7), and a murine mastitis model with BALB/C mice, we evaluated the safety and efficacy of Colo EVs, in vivo and in vitro. Colo EVs had favorable biosafety profiles, promoting cell proliferation and migration without inducing pathological changes after injection into murine mammary glands. In LPS-induced murine mastitis, Colo EVs significantly reduced inflammation, improved inflammatory scores, and preserved tight junction proteins while protecting milk production. Additionally, in vitro experiments demonstrated that Colo EVs downregulated inflammatory cytokine expression, reduced inflammatory markers, and attenuated NF-κB pathway activation. In summary, we inferred that Colo EVs have promise as a therapeutic approach for mastitis treatment, owing to their anti-inflammatory properties, potentially mediated through the NF-κB signaling pathway modulation.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467819","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}
Gliomas are one of the most frequent primary brain tumors and pose a serious threat to people's lives and health. Platelets, a crucial component of blood, have been applied as drug delivery carriers for disease diagnosis and treatment. In this study, we designed engineered nanoplatelets for targeted delivery of therapeutic miR-375 and temozolomide (TMZ, a first-line glioma treatment agent) to enhance glioma therapy. Nanoplatelets were prepared through mild ultrasound, TMZ and miR-375 were co-loaded through ultrasound and electrostatic interactions, respectively, to combine chemotherapy with gene therapy against glioma. To improve the blood brain barrier (BBB) crossing efficiency and glioma targeting ability, the nanoplatelets were modified with central nervous system-specific rabies viral glycoprotein peptide (RVG) through thiol-maleimide click reaction. The RVG modified nanoplatelets co-loaded TMZ and miR-375 (NR/TMZ/miR-375) not only inherited the good stability and remarkable biocompatibility of platelets, but also promoted the cellular uptake and penetration of glioma tissues, and effectively induced cell apoptosis to enhance the therapeutic effect of drugs. In vivo studies showed that NR/TMZ/miR-375 significantly increased the circulation time of TMZ, and exhibited superior combined antitumor effects. In summary, this multifunctional 'natural' nanodrug delivery system provides a potent, scalable, and safety approach for platelet-based combined cancer chemotherapy and gene therapy.
{"title":"Nanoplatelets modified with RVG for targeted delivery of miR-375 and temozolomide to enhance gliomas therapy.","authors":"Tingting Yang, Nan Zhang, Yuanyuan Liu, Ruyue Yang, Zhaoyi Wei, Futai Liu, Dan Song, Longwei Wang, Jiangyan Wei, Yuanpei Li, Deliang Shen, Gaofeng Liang","doi":"10.1186/s12951-024-02895-6","DOIUrl":"https://doi.org/10.1186/s12951-024-02895-6","url":null,"abstract":"<p><p>Gliomas are one of the most frequent primary brain tumors and pose a serious threat to people's lives and health. Platelets, a crucial component of blood, have been applied as drug delivery carriers for disease diagnosis and treatment. In this study, we designed engineered nanoplatelets for targeted delivery of therapeutic miR-375 and temozolomide (TMZ, a first-line glioma treatment agent) to enhance glioma therapy. Nanoplatelets were prepared through mild ultrasound, TMZ and miR-375 were co-loaded through ultrasound and electrostatic interactions, respectively, to combine chemotherapy with gene therapy against glioma. To improve the blood brain barrier (BBB) crossing efficiency and glioma targeting ability, the nanoplatelets were modified with central nervous system-specific rabies viral glycoprotein peptide (RVG) through thiol-maleimide click reaction. The RVG modified nanoplatelets co-loaded TMZ and miR-375 (NR/TMZ/miR-375) not only inherited the good stability and remarkable biocompatibility of platelets, but also promoted the cellular uptake and penetration of glioma tissues, and effectively induced cell apoptosis to enhance the therapeutic effect of drugs. In vivo studies showed that NR/TMZ/miR-375 significantly increased the circulation time of TMZ, and exhibited superior combined antitumor effects. In summary, this multifunctional 'natural' nanodrug delivery system provides a potent, scalable, and safety approach for platelet-based combined cancer chemotherapy and gene therapy.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467831","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}
Pub Date : 2024-10-15DOI: 10.1186/s12951-024-02894-7
Jiahao Zhang, Xi Ren, Zhaoyang Nie, Yue You, Yao Zhu, Hui Chen, Haichuan Yu, Gaozhi P Mo, Lianjiu Su, Zhiyong Peng, Man-Chung Tang
Ischemia/reperfusion (I/R) is an important inducer of acute kidney injury (AKI), and triggers the generation of reactive oxygen species (ROS) and the expression of matrix metalloproteinase 2 (MMP2), exacerbating kidney damage. Given the immense potential of vitamin E (VitE) as a natural fat-soluble antioxidant in kidney protection, we designed the nanoparticles (NPs) that could dual respond to ROS and MMP2, aiming to accurately deliver VitE to renal injury cells. The NPs utilized Gel-SH as a sensitive receptor for MMP2 and diselenide as a sensitive receptor for ROS, while PEG2k modification enhanced biocompatibility and prevented phagocytosis mediated by the mononuclear phagocyte system. The amphiphilic Gel-SH and diselenide encapsulate the liposoluble VitE and self-assemble into the NPs with a hydrodynamic size of 69.92 nm. Both in vivo and in vitro experiments based on these NPs show good biocompatibility and the ability of target renal injury cells. In vivo kidney I/R injury models and in vitro cell hypoxia/reoxygenation models, the NPs have demonstrated effects in reducing oxidative stress and alleviating AKI. Notably, VitE can preferentially react with peroxyl radical (LOO•) than polyunsaturated fatty acid (PUFA), inhibiting the formation of carbon centered radical (L•), thereby blocking the chain reaction between PUFA and LOO• in ferroptosis. The NPs also inhibit the transition from AKI to chronic kidney disease, with few side effects. Thus, the NPs with dual-responsiveness to MMP2 and ROS for targeted delivery of VitE to renal injury cells exhibit remarkable effects in inhibiting ROS and the chain reactions of ferroptosis, making it a promising therapeutic agent against AKI caused by I/R.
{"title":"Dual-responsive renal injury cells targeting nanoparticles for vitamin E delivery to treat ischemia reperfusion-induced acute kidney injury.","authors":"Jiahao Zhang, Xi Ren, Zhaoyang Nie, Yue You, Yao Zhu, Hui Chen, Haichuan Yu, Gaozhi P Mo, Lianjiu Su, Zhiyong Peng, Man-Chung Tang","doi":"10.1186/s12951-024-02894-7","DOIUrl":"https://doi.org/10.1186/s12951-024-02894-7","url":null,"abstract":"<p><p>Ischemia/reperfusion (I/R) is an important inducer of acute kidney injury (AKI), and triggers the generation of reactive oxygen species (ROS) and the expression of matrix metalloproteinase 2 (MMP2), exacerbating kidney damage. Given the immense potential of vitamin E (VitE) as a natural fat-soluble antioxidant in kidney protection, we designed the nanoparticles (NPs) that could dual respond to ROS and MMP2, aiming to accurately deliver VitE to renal injury cells. The NPs utilized Gel-SH as a sensitive receptor for MMP2 and diselenide as a sensitive receptor for ROS, while PEG<sub>2k</sub> modification enhanced biocompatibility and prevented phagocytosis mediated by the mononuclear phagocyte system. The amphiphilic Gel-SH and diselenide encapsulate the liposoluble VitE and self-assemble into the NPs with a hydrodynamic size of 69.92 nm. Both in vivo and in vitro experiments based on these NPs show good biocompatibility and the ability of target renal injury cells. In vivo kidney I/R injury models and in vitro cell hypoxia/reoxygenation models, the NPs have demonstrated effects in reducing oxidative stress and alleviating AKI. Notably, VitE can preferentially react with peroxyl radical (LOO•) than polyunsaturated fatty acid (PUFA), inhibiting the formation of carbon centered radical (L•), thereby blocking the chain reaction between PUFA and LOO• in ferroptosis. The NPs also inhibit the transition from AKI to chronic kidney disease, with few side effects. Thus, the NPs with dual-responsiveness to MMP2 and ROS for targeted delivery of VitE to renal injury cells exhibit remarkable effects in inhibiting ROS and the chain reactions of ferroptosis, making it a promising therapeutic agent against AKI caused by I/R.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467821","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}
The hypertrophic scar (HS) is a prevalent cutaneous fibrotic disorder that impacts both the aesthetic and functional aspects of the skin, there is an urgent need for a highly safe and effective approach to address the challenge of HS with thick and deep types. Inspired by the superior deep tissue penetrative ability of near-infrared-II (NIR-II) light and potential mitochondria ROS inducing effect of Chinese medicine lycorine (LYC), we fabricated a Cu2Se@LYC (CL) composite by encapsulating LYC on polyvinyl pyrrolidone (PVP) modified Cu2Se nanoparticles. After NIR-II irradiation, CL could induce the generation of reactive oxygen species (ROS) and mitochondrial damage in hypertrophic scar fibroblasts (HSFs). The subsequent release of cytochrome C (cyt-c) from mitochondria into the cytoplasm and upregulation of beclin1 leads to the activation of endogenous apoptosis and autophagy-mediated cell death. The CL + NIR-II treatment exhibited a pronounced anti-scarring effect in both in vitro and in vivo rabbit ear scar models, leading to a significant reduction in the fibrotic markers including Collagen I/III and α-smooth muscle actin (α-SMA). This study comprehensively investigated the crucial role of HSFs' autophagy in scar management and proposed a safe and effective therapy based on NIR-II laser for clinical application.
{"title":"NIR-II light based combinatorial management of hypertrophic scar by inducing autophagy in fibroblasts.","authors":"Yunxian Dong, Haibin Wang, Youliang Zhang, Yanqun Wu, Ling Lu, Hao Yu, Lingcong Zhou, Peng Zhao, Sixue Ouyang, Zibin Song, Zhicheng Hu, Dongming Lv, Yanchao Rong, Zirui Zhao, Jia Tao, Bing Tang, Shengkang Luo","doi":"10.1186/s12951-024-02876-9","DOIUrl":"https://doi.org/10.1186/s12951-024-02876-9","url":null,"abstract":"<p><p>The hypertrophic scar (HS) is a prevalent cutaneous fibrotic disorder that impacts both the aesthetic and functional aspects of the skin, there is an urgent need for a highly safe and effective approach to address the challenge of HS with thick and deep types. Inspired by the superior deep tissue penetrative ability of near-infrared-II (NIR-II) light and potential mitochondria ROS inducing effect of Chinese medicine lycorine (LYC), we fabricated a Cu<sub>2</sub>Se@LYC (CL) composite by encapsulating LYC on polyvinyl pyrrolidone (PVP) modified Cu<sub>2</sub>Se nanoparticles. After NIR-II irradiation, CL could induce the generation of reactive oxygen species (ROS) and mitochondrial damage in hypertrophic scar fibroblasts (HSFs). The subsequent release of cytochrome C (cyt-c) from mitochondria into the cytoplasm and upregulation of beclin1 leads to the activation of endogenous apoptosis and autophagy-mediated cell death. The CL + NIR-II treatment exhibited a pronounced anti-scarring effect in both in vitro and in vivo rabbit ear scar models, leading to a significant reduction in the fibrotic markers including Collagen I/III and α-smooth muscle actin (α-SMA). This study comprehensively investigated the crucial role of HSFs' autophagy in scar management and proposed a safe and effective therapy based on NIR-II laser for clinical application.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467833","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}