Tumor Microenvironment‐Induced Drug Depository for Persistent Antitumor Chemotherapy and Immune Activation

Abstract Herein, a drug‐loading nanosystem that can in situ form drug depository for persistent antitumor chemotherapy and immune regulation is designed and built. The system (DOX@MIL‐LOX@AL) is fabricated by packaging alginate on the surface of Doxorubicin (DOX) and lactate oxidase (LOX) loaded MIL‐101(Fe)‐NH 2 nanoparticle, which can easily aggregate in the tumor microenvironment through the cross‐linking with intratumoral Ca 2+ . Benefiting from the tumor retention ability, the fast‐formed drug depository will continuously release DOX and Fe ions through the ATP‐triggered slow degradation, thus realizing persistent antitumor chemotherapy and immune regulation. Meanwhile, LOX in the non‐aggregated nanoparticles is able to convert the lactic acid to H 2 O 2 , which will be subsequently decomposed into ·OH by Fe ions to further enhance the DOX‐induced immunogenic death effect of tumor cells. Together, with the effective consumption of immunosuppressive lactic acid, long‐term chemotherapy, and oxidation therapy, DOX@MIL‐LOX@AL can execute high‐performance antitumor chemotherapy and immune activation with only one subcutaneous administration.