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

Abstract

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 <i>in vivo</i>. 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 (Fe₃(CO)₁₂), and radical-degradable 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 <i>via</i> 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(<i>N</i>,<i>N</i>-diethyl dithiocarbamato)copper(II) chelates to synergize the therapeutic effect to ablate deep-seated orthotopic gastric tumors.