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

Macrophage membrane biomimetic nanoparticles M@HCDA can target damaged myocardium and co-deliver siADAM17 and Celastrol. • Treatment of M@HCDA in vitro and in vivo suppressed doxorubicin-induced mitochondrial injury and rescued cardiac function. • M@HCDA improves doxorubicin-induced ferroptosis by targeting and delivering Celastrol to regulate GPX4 and SLC7A11. • M@HCDA alleviates doxorubicin-induced inflammation by inhibiting the MAPK signaling through targeted delivery of siADAM17. 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. Download: Download high-res image (610KB) Download: Download full-size image