LAUSR

Mitochondrial dysfunction of cardiomyocytes (CMs) has been identified as a significant pathogenesis of early myocardial infarction (MI). However, only a few agents or strategies have been developed to improve mitochondrial dysfunction for the effective MI treatment. Herein, a reactive oxygen species (ROS)‐responsive PAMB‐G‐TK/4‐arm‐PEG‐SG hydrogel is developed for localized drug‐loaded liposome delivery. Notably, the liposomes contain both elamipretide (SS‐31) and sphingosine‐1‐phosphate (S1P), where SS‐31 acts as an inhibitor of mitochondrial oxidative damage and S1P as a signaling molecule for activating angiogenesis. Liposome‐encapsulated PAMB‐G‐TK/4‐arm‐PEG‐SG hydrogels demonstrate myocardium‐like mechanical strength and electrical conductivity, and ROS‐sensitive release of SS‐31 and S1P‐loaded liposomes. Further liposomal release of SS‐31, which can target cytochrome c in the mitochondrial inner membrane of damaged CMs, inhibits pathological ROS production, improving mitochondrial dysfunction. Meanwhile, S1P released from the liposome induces endothelial cell angiogenesis by activating the S1PR1/PI3K/Akt pathway. In a rat MI model, the resulting liposomal composite hydrogel improves cardiac function by scavenging excess ROS, improving mitochondrial dysfunction, and promoting angiogenesis. This study reports for the first time a liposomal composite hydrogel that can directly target mitochondria of damaged CMs for a feedback‐regulated release of encapsulated liposomes to consume the overproduced pathological ROS for improved CM activity and enhanced MI treatment.