Dual-Responsive multifunctional “core–shell” magnetic nanoparticles promoting Fenton reaction for tumor ferroptosis therapy

Ferroptosis is a newly found promising cell death pathway, which bypasses apoptosis and overcomes multidrug resistance of tumor. In this study, acid and redox dual-responsive multifunctional magnetic nanoparticles loading with Sorafenib (Sor), namely FMMHG/Sor, were prepared for tumor ferroptosis therapy. Fe3O4 nanoparticles as the core provided sufficient iron ion for ferroptosis and magnetic targeting. Mesoporous organosilica nanoparticles (MON) was coated on the outside of Fe3O4 to form "core-shell" structure, which contained the disulfidebond with redox-responsive. MnO2 was dropped on the surface of MON as gatekeeper, which was decomposed at low pH into O2 to promote drug release. Glucose oxidase (GOD) catalyzed glucose to produce H2O2, which reacted with iron ion to generate hydroxylradical (OH•) vie Fenton reaction. OH• inhibited GPX4 expression to induce ferroptosis with Sor as a synergistic inducer. Hyaluronic acid (HA) protected nanoparticles from removed by immune system and actively targeted to tumor cells. Overall, pH and redox dual-responsive FMMHG/Sor is a promising antitumor nanomedicine with magnetic targeting and active targeting for efficient tumor ferroptosis therapy.