Injectable Magnolol-Peptide Hydrogel as a Minimally Invasive Treatment for Doxorubicin-Induced Cardiomyopathy via Inhibition of Aberrant Mitochondrial Fission

Doxorubicin (DOX), an effective anthracycline chemotherapeutic agent, faces clinical limitations due to dose-dependent cardiotoxicity that can progress to irreversible DOX-induced cardiomyopathy (DIC). This pathology is driven by mitochondrial dysfunction, with the DOX-induced hyperactivation of mitochondrial fission as a central pathological event in DIC, leading to oxidative stress and cardiomyocyte apoptosis. To address this, we developed an injectable, self-assembling peptide-drug conjugate hydrogel, Mag-Gel, for mitochondrial targeted therapy. This system enables precise intramyocardial delivery via ultrasound-guided percutaneous injection, overcoming the translational barrier of conventional invasive hydrogels by eliminating the need for invasive surgery. In vitro, Mag-Gel attenuated aberrant mitochondrial fission by upregulating Sirt3 expression 5.76-fold and enhancing inhibitory phosphorylation of DRP1 at Ser637 2.33-fold, thereby reducing reactive oxygen species (ROS) accumulation and suppressing apoptosis in cardiomyocytes. In a murine DIC model, Mag-Gel ensured sustained myocardial retention and significantly improved cardiac function, enhancing the ejection fraction and reducing fibrosis compared to free drug treatment. This work presents a clinically feasible, minimally invasive strategy for treating DIC by targeting mitochondrial homeostasis, offering a practical approach to mitigating DOX-related myocardial injury.