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.