Degradable Nanoregulators Based on Ultra‐Small Ferrous Sulfide for Photoacoustic/Magnetic Resonance Imaging‐Guided Tumor Starvation and Ferroptosis

Abstract Malignant tumors pose a great threat to human health due to their abnormal vascular system and high interstitial density, leading to high invasiveness and low curability. Tumor vasodilation and ensuring deep drug delivery are essential to elevating tumor elimination efficiency. Herein, a powerful nanoregulator is reported with tumor vessel vasodilation and tumor microenvironment (TME) reconstruction capacity for photoacoustic/magnetic resonance imaging‐guided tumor starvation and ferroptosis therapy. This nanoregulator uses ultra‐small ferrous sulfide (FeS) nanoparticles as a Fenton agent and hydrogen sulfide (H 2 S) as a donor. Additionally, glucose oxidase (GOx) serves as a glucose‐depleting agent and poly (lactic‐co‐glycolic) acid (PLGA) functions as a building block. PLGA@ultra‐small FeS‐GOx nanoregulators can simultaneously promote accumulation and enhance penetration deep into tumors through H 2 S‐induced vasodilation and acid‐responsive degradation. Further, the TME can be regulated toward aggravated acidity, hydrogen peroxide up‐regulation, glutathione down‐regulation, and triphosadenine down‐regulation by the released ferrous ion (Fe 2+ ), H 2 S, and GOx. A large amount of lipid hydroperoxides (LPOs) accumulate in this antioxidant system‐disabled microenvironment through the Fe 2+ ‐mediated Fenton reaction. In vivo data reveal that this synergistic energy depletion‐induced starvation and LPO accumulation‐driven ferroptosis efficiently kill tumor cells. This approach can guide the development of nanomedicines with clinical translation potential.