A bidirectional pyroptosis regulation strategy to resolve cardiotoxicity-antitumor efficacy dilemma of doxorubicin.
Xu Hanying H, Zhang Yi Y, Guo Hao H, Shao Zhong Z et al.
Doxorubicin (DOX), a frontline chemotherapeutic agent, is severely limited by reactive oxygen species (ROS) overload-mediated cardiotoxicity involving multiple programmed cell death pathways, with pyroptosis validated as one major mechanism, whereas conventional cardioprotective interventions may compromise antitumor efficacy. Here, we report a selectively redox-responsive approach based on self-crosslinked lipoic acid nanoparticles (LANPs) that enables bidirectional pyroptosis regulation in cardiac vs. tumor tissues, achieving concurrent cardioprotection and antitumor sensitization during DOX therapy. In cardiomyocytes, LANPs degrade into the lipoic acid (LA)/dihydrolipoic acid (DHLA) pair, which exerts anti-oxidant activity to scavenge excessive ROS, thereby mitigating oxidative stress-associated pyroptosis and subsequent cardiac injury. In cancer cells with a relatively high reducing environment, LANP degradation predominantly yields DHLA, which promotes ROS accumulation, thereby enhancing pyroptosis-associated antitumor efficacy. In female BALB/c mouse models, LANPs afford cardioprotection comparable to dexrazoxane (DEX), the only clinically approved cardioprotective agent against DOX, while additionally alleviating systemic toxicity, particularly bone marrow suppression, an advantage not afforded by DEX. As expected, LANPs not only preserve but also potentiate DOX-induced antitumor efficacy. This study establishes LANPs as a promising adjuvant strategy for expanding the scope of chemotherapeutic applications beyond DOX.