Zhang, Y.; Li, W.; Xiao, Y.; Luo, L.; Ai, J.; Mo, S.; Li, L.; Deng, J.; Wang, X.; Li, Q.; Zeng, Y.; Liu, H.; Wang, F.; Li, Z.

Doxorubicin (Dox)-induced cardiotoxicity represents a significant clinical adverse effect associated with cancer chemotherapy treatment. The systematic toxicity associated with the currently available drug dexrazoxane has limited its clinical utility. Inspired by cancer drug resistance mechanisms, we propose a novel strategy termed Transient overexpression of p-glycoprotein (P-gp) for Cardiac reprogramming (TopCare) to induce cardiac drug resistance as a treatment for cardiotoxicity. This approach involves reprogramming cardiomyocytes by delivering lipid nanoparticles (LNPs)-based mRNA therapeutics to induce temporary P-gp overexpression, which in turn reduces intracellular Dox levels and suppresses cytotoxic effects. Our results demonstrated that LNPs with P-gp mRNAs (P-gp LNPs) enhance P-gp expression in H9c2 cells, significantly lowering the cytotoxicity of both Dox and paclitaxel (PTX). In a mouse model with Dox-induced cardiotoxicity, it was observed that P-gp LNPs effectively promoted P-gp overexpression in cardiomyocytes, with a time-dependent decline in P-gp protein levels. This TopCare strategy resulted in improved survival rates, restored cardiac function, and reduced myocardial fibrosis and structural cardiac alterations. Furthermore, studies in large animals have shown that intrapericardial (iPC) injection of P-gp LNPs effectively mitigates adverse effects and restores cardiac function in pig models of Dox-induced cardiotoxicity. The significant cardioprotective effects achieved through cardiac drug resistance highlight the safety, efficacy, and clinical potential of the TopCare strategy for alleviating doxorubicin-induced cardiotoxicity.