A ROS-Responsive Polymer-Micelle Delivery System Designed for the Treatment of Drug-Induced Myocarditis

Background/Objectives: Drug-induced myocarditis lacks targeted therapies. Current glucocorticoid and immunosuppressant treatments suffer from poor lesion accumulation and systemic toxicity. We aimed to develop a ROS-responsive self-assembled nanocarrier (GSP) for the controlled release of glycyrrhetinic acid (GA) to inflamed myocardial tissue. Methods: GSP was synthesized by conjugating GA and PEG via a thioketal linker. Micelles were characterized by NMR, DLS, and TEM. ROS-triggered drug release, cytotoxicity, cellular uptake, anti-inflammatory (TNF-α) and ROS-scavenging effects were evaluated in DOX-activated H9C2 cells. In vivo, biodistribution, echocardiography, inflammatory cytokines, and histopathology were assessed in an isoproterenol-induced mouse myocarditis model. Results: GSP exhibited ROS-dependent release (>80% GA within 48 h under 100 mM H₂O₂ vs. <20% without). In vitro, GSP significantly reduced TNF-α and intracellular ROS in activated cardiomyocytes compared to free GA or non-responsive controls. In vivo, GSP showed enhanced cardiac accumulation via the EPR effect and markedly improved left ventricular ejection fraction and fractional shortening, reduced serum TNF-α, IL-1β, and IL-6, and decreased collagen deposition, with good biocompatibility. Conclusions: The ROS-responsive GSP nanocarrier enables on-demand drug release in the inflamed myocardial microenvironment, effectively attenuating inflammation and improving cardiac function, representing a promising targeted strategy for drug-induced myocarditis.