OBJECTIVE: Heart failure (HF) is a prevalent, refractory, and costly medical condition. As most current strategies have failed to yield beneficial clinical outcomes, microenvironment-responsive micelles have been developed to target cardiomyocyte mitochondria to improve HF. METHODS: In this paper, we constructed reactive oxygen species (ROS)-responsive triphenylphosphine (TPP)-modified tanshinone IIA (TIIA) micelles (TK-TPP-TIIA@Ms). TIIA was encapsulated within the micelles and utilized TPP-conjugated DSPE-PEG RESULTS: TK-TPP-TIIA@Ms was successfully prepared and exhibited normal appearance and morphology, appropriate particle size, and zeta potential
and demonstrated good encapsulation efficiency, drug loading, and biological safety. In vitro studies showed that TK-TPP-TIIA@Ms had strong uptake ability in H9c2 cells, which led to reduced DOX-induced ROS expression, decreased secretion of inflammatory factors, inhibition of cell apoptosis, and restoration of normal mitochondrial membrane potential. In vivo, TK-TPP-TIIA@Ms effectively ameliorated DOX-induced myocardial tissue damage, reduced cell apoptosis, decreased the expression of inflammatory factors, and improved oxidative stress, which inhibited DOX-induced HF in mice. CONCLUSION: TK-TPP-TIIA@Ms is an effective and safe strategy for the targeted therapy of heart diseases and is expected to become a potential treatment for heart failure.