{"title":"恢复线粒体稳态的肽-药物偶联物与ros反应性NO释放能力用于心肌梗死的靶向治疗。","authors":"Zhaoyang Lu, Quanyou Chai, Wenbin Dai, Bo Yu, Qingbo Lv, Fuyu Qiu, Jing Gao, Juhong Zhang, Xiaohua Shen, Shengyu Chen, Zhida Shen, Min Shang, Wenbin Zhang, Guosheng Fu, Qiao Jin, Yanbo Zhao, Fan Jia","doi":"10.1186/s12951-025-03578-6","DOIUrl":null,"url":null,"abstract":"<p><p>Myocardial infarction (MI) is the leading cause of death worldwide. Exogenous delivery of nitric oxide (NO) shows great potential in MI treatment. However, the burst generation of reactive oxygen species (ROS) in ischemic microenvironment of MI oxidize NO to harmful peroxynitrite (ONOO<sup>-</sup>). It renders secondary damage to cardiomyocyte, causing the failure of NO based therapies. Herein, we proposed an ROS responsive peptide-drug conjugates (PDCs) to overcome the dilemma of NO based therapy. The conjugated cardiac injury targeting peptide (CTP) in the PDC (named CTP-PBA-ISN) promoted selective accumulation of drugs in MI sites. Besides, controlled release of NO prodrug isosorbide mononitrate (ISN) was achieved by pathological ROS triggered hydrolysis of boronate ester. Meanwhile the antioxidant byproduct 4-hydroxybenzyl alcohol further scavenges the overwhelming ROS, reducing the production of RNS and improving the bioavailability of NO. The CTP-PBA-ISN efficiently inhibited myocardial apoptosis, improved myocardial function, and ameliorated adverse cardiac remodeling post-MI in mice by relief of oxidative stress, promotion of angiogenesis and restoration of mitochondrial homeostasis and function. These findings prove that the synergic ROS regulation is essential in maximizing therapeutic effects of NO. Our CTP-PBA-ISN may serve as a valuable inspiration for development of other treatments of myocardial infarction and other ischemic diseases.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"496"},"PeriodicalIF":10.6000,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236005/pdf/","citationCount":"0","resultStr":"{\"title\":\"Mitochondrial homeostasis restoring peptide-drug conjugates with ROS-responsive NO releasing ability for targeted therapy of myocardial infarction.\",\"authors\":\"Zhaoyang Lu, Quanyou Chai, Wenbin Dai, Bo Yu, Qingbo Lv, Fuyu Qiu, Jing Gao, Juhong Zhang, Xiaohua Shen, Shengyu Chen, Zhida Shen, Min Shang, Wenbin Zhang, Guosheng Fu, Qiao Jin, Yanbo Zhao, Fan Jia\",\"doi\":\"10.1186/s12951-025-03578-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Myocardial infarction (MI) is the leading cause of death worldwide. Exogenous delivery of nitric oxide (NO) shows great potential in MI treatment. However, the burst generation of reactive oxygen species (ROS) in ischemic microenvironment of MI oxidize NO to harmful peroxynitrite (ONOO<sup>-</sup>). It renders secondary damage to cardiomyocyte, causing the failure of NO based therapies. Herein, we proposed an ROS responsive peptide-drug conjugates (PDCs) to overcome the dilemma of NO based therapy. The conjugated cardiac injury targeting peptide (CTP) in the PDC (named CTP-PBA-ISN) promoted selective accumulation of drugs in MI sites. Besides, controlled release of NO prodrug isosorbide mononitrate (ISN) was achieved by pathological ROS triggered hydrolysis of boronate ester. Meanwhile the antioxidant byproduct 4-hydroxybenzyl alcohol further scavenges the overwhelming ROS, reducing the production of RNS and improving the bioavailability of NO. The CTP-PBA-ISN efficiently inhibited myocardial apoptosis, improved myocardial function, and ameliorated adverse cardiac remodeling post-MI in mice by relief of oxidative stress, promotion of angiogenesis and restoration of mitochondrial homeostasis and function. These findings prove that the synergic ROS regulation is essential in maximizing therapeutic effects of NO. Our CTP-PBA-ISN may serve as a valuable inspiration for development of other treatments of myocardial infarction and other ischemic diseases.</p>\",\"PeriodicalId\":16383,\"journal\":{\"name\":\"Journal of Nanobiotechnology\",\"volume\":\"23 1\",\"pages\":\"496\"},\"PeriodicalIF\":10.6000,\"publicationDate\":\"2025-07-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236005/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Nanobiotechnology\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://doi.org/10.1186/s12951-025-03578-6\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Nanobiotechnology","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1186/s12951-025-03578-6","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Mitochondrial homeostasis restoring peptide-drug conjugates with ROS-responsive NO releasing ability for targeted therapy of myocardial infarction.
Myocardial infarction (MI) is the leading cause of death worldwide. Exogenous delivery of nitric oxide (NO) shows great potential in MI treatment. However, the burst generation of reactive oxygen species (ROS) in ischemic microenvironment of MI oxidize NO to harmful peroxynitrite (ONOO-). It renders secondary damage to cardiomyocyte, causing the failure of NO based therapies. Herein, we proposed an ROS responsive peptide-drug conjugates (PDCs) to overcome the dilemma of NO based therapy. The conjugated cardiac injury targeting peptide (CTP) in the PDC (named CTP-PBA-ISN) promoted selective accumulation of drugs in MI sites. Besides, controlled release of NO prodrug isosorbide mononitrate (ISN) was achieved by pathological ROS triggered hydrolysis of boronate ester. Meanwhile the antioxidant byproduct 4-hydroxybenzyl alcohol further scavenges the overwhelming ROS, reducing the production of RNS and improving the bioavailability of NO. The CTP-PBA-ISN efficiently inhibited myocardial apoptosis, improved myocardial function, and ameliorated adverse cardiac remodeling post-MI in mice by relief of oxidative stress, promotion of angiogenesis and restoration of mitochondrial homeostasis and function. These findings prove that the synergic ROS regulation is essential in maximizing therapeutic effects of NO. Our CTP-PBA-ISN may serve as a valuable inspiration for development of other treatments of myocardial infarction and other ischemic diseases.
期刊介绍:
Journal of Nanobiotechnology is an open access peer-reviewed journal communicating scientific and technological advances in the fields of medicine and biology, with an emphasis in their interface with nanoscale sciences. The journal provides biomedical scientists and the international biotechnology business community with the latest developments in the growing field of Nanobiotechnology.