Targeted delivery of celastrol and siRNA via macrophage biomimetic nanoparticles for doxorubicin-induced cardiomyopathy therapy

Doxorubicin-induced cardiomyopathy (DIC) is a severe complication following anthracycline chemotherapy, and its main pathogenesis is inflammatory responses and ferroptosis. This study constructed hyaluronic acid-based macrophage biomimetic nanoparticles (M@HCDA) to co-delivery of Celastrol (Cel) and siADAM17 for the treatment of DIC. This research revealed that Cel exerted an anti-ferroptosis effect by regulating GPX4 and SLC7A11, while siADAM17 inhibited TAK1-MAPK pathway activation by silencing ADAM17. Meanwhile, the synergistic effect of Cel and siADAM17 significantly alleviated oxidative stress, myocardial fibrosis, apoptosis, and mitochondrial dysfunction, thereby relieving myocardial injury caused by DOX-induced cardiotoxicity and providing effective early cardioprotection. In vitro and in vivo experiments indicated that M@HCDA exhibited good stability, biocompatibility, and targeting capability, showing the clinical application potential. The design and development of M@HCDA provide new experimental evidence and candidate strategy for treating DIC.