Degradable FeCuS-Lipid Nanoparticles Confer Ultrasound-Activated CO Release and O2-Independent Radical Production for Synergistic Therapy

Ultrasound (US)-activated nanoagents capable of producing cytotoxic species have been promising for the treatment of deep-seated tumors; however, poor tumor uptake and insufficient generation of cytotoxic agents have largely limited their therapeutic efficacy in vivo. Herein, we report a hybrid FeCuS-lipid nanoparticle (AIBA@FeCuS-FeCO) by amphiphilic lipids-assisted emulsion of a free radical initiator (AIBA), a radical-sensitive CO donor (Fe-3(CO)(12)), and radicaldegradable FeCuS nanodisks for US-activated synergistic therapy of deep-located orthotopic gastric tumors in living mice. Upon US irradiation, AIBA@FeCuS-FeCO could be degraded and release cytotoxic AIBA radicals, CO, Fe2+, and Cu2+, allowing us to (1) enhance tumor uptake of AIBA@FeCuS-FeCO through CO-mediated vasodilation, (2) promote hydroxyl radical production and induce tumor ferroptosis via intracellular accumulation of Fe2+/Cu2+, and (3) kill tumor cells. Moreover, the subsequent administration of disulfiram (DSF) could further chelate with the liberated Cu2+, yielding toxic bis(N,N-diethyl dithiocarbamato)copper(II) chelates to synergize the therapeutic effect to ablate deep-seated orthotopic gastric tumors.

Automated summary

The US-activated hybrid FeCuS-lipid nanoparticles showed promising therapeutic efficacy in deep-located orthotopic gastric tumors in living mice, enhancing tumor uptake and promoting hydroxyl radical production to induce tumor ferroptosis. The addition of disulfiram further synergized the therapeutic effect by chelating with liberated Cu2+ and yielding toxic chelates to ablate deep-seated orthotopic gastric tumors.