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. Fe 3 O 4 nanoparticles as the core provided sufficient iron ion for ferroptosis and magnetic targeting. Mesoporous organosilica nanoparticles (MON) was coated on the outside of Fe 3 O 4 to form “core–shell” structure, which contained the disulfide   bond with redox-responsive. MnO 2 was dropped on the surface of MON as gatekeeper, which was decomposed at low pH into O 2 to promote drug release. Glucose oxidase (GOD) catalyzed glucose to produce H 2 O 2 , which reacted with iron ion to generate hydroxyl   radical (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.