Cardiac reprogramming via transient overexpression of P-glycoprotein alleviates doxorubicin-induced cardiotoxicity in mice and pigs

Doxorubicin-induced cardiotoxicity represents a significant clinical adverse effect associated with cancer chemotherapy treatment. Inspired by cancer drug resistance mechanisms, we propose a novel strategy termed transient overexpression of p-glycoprotein for cardiac reprogramming to induce cardiac drug resistance as a treatment for cardiotoxicity. This approach involves reprogramming cardiomyocytes by delivering lipid nanoparticles-based mRNA therapeutics to induce temporary p-glycoprotein overexpression, which in turn reduces intracellular doxorubicin levels and suppresses cytotoxic effects. This strategy results in promoted p-glycoprotein overexpression in cardiomyocytes, improved survival rates, restored cardiac function, and reduced myocardial fibrosis and structural cardiac alterations in a mouse model with doxorubicin-induced cardiotoxicity. Furthermore, studies in large animals show that intrapericardial injection of lipid nanoparticles with p-glycoprotein mRNAs effectively mitigates adverse effects and restores cardiac function in male pig models of doxorubicin-induced cardiotoxicity. The significant cardioprotective effects achieved through cardiac drug resistance highlight the safety, efficacy, and clinical potential of this strategy for alleviating doxorubicin-induced cardiotoxicity. Doxorubicin-induced cardiotoxicity represents a critical adverse event in clinical cancer chemotherapy. Here, the authors show that cardiac administration of P-glycoprotein mRNA loaded lipid nanoparticles induces cardiac reprogramming and drug resistance, thereby effectively alleviating doxorubicin-induced cardiotoxicity in mice and pigs.