Cinobufagin loaded Prussian blue-like nanoparticles for chemo/gas therapy of multidrug resistant cancer

Tumor multidrug resistance (MDR) presents a major challenge to the efficacy of cancer chemotherapy. Pyroptosis, a form of regulated cell death distinct from apoptosis and unassociated with drug resistance, may restore tumor cells’ sensitivity to therapeutic drugs. Cinobufagin (CS-1) with efficient pyroptosis inducing capability showed the potential for the treatment of MDR cancer. However, the hydrophobic nature, low bioavailability, and possible toxic side effects under high dosage pose significant limitations on its clinical application. In this research endeavor, we have engineered a unique “chemo-gas” hybrid nanocomplexes (HA@Lip-CS-1@PBCO NPs) by wrapping CS-1 containing lipofilm onto manganese carbonyl hybrid Prussian blue nanoparticles (PBCO NPs) and modifying the targeting molecule HA on the surface. In vitro studies demonstrated that HA@Lip-CS-1@PBCO NPs, exhibiting high tumor-targeting capability, effectively induced pyroptosis in MCF-7/ADR cells through the Caspase-3/GSDME signaling pathway. In vivo assays indicated a strong inhibitory effect on MDR tumors with low CS-1 cardiotoxicity. In conclusion, this “chemo-gas” integrated therapy provides a new strategy for treating MDR tumors.