A Tumor‐Microenvironment‐Responsive Nanocomposite for Hydrogen Sulfide Gas and Trimodal‐Enhanced Enzyme Dynamic Therapy

Abstract Recently, enzyme dynamic therapy (EDT) has drawn much attention as a new type of dynamic therapy. However, the selection of suitable nanocarriers to deliver chloroperoxidase (CPO) and enhancement of the level of hydrogen peroxide (H 2 O 2 ) in the tumor microenvironment (TME) are critical factors for improving the efficiency of EDT. In this study, a rapidly decomposing nanocomposite is designed using tetra‐sulfide‐bond‐incorporating dendritic mesoporous organosilica (DMOS) as a nanocarrier, followed by loading CPO and sodium‐hyaluronate‐modified calcium peroxide nanoparticles (CaO 2 ‐HA NPs). The nanocomposite can effectively generate singlet oxygen ( 1 O 2 ) for tumor therapy without any exogenous stimulus via trimodal‐enhanced EDT, including DMOS‐induced depletion of glutathione (GSH), H 2 O 2 compensation from CaO 2 ‐HA NPs in mildly acidic TME, and oxidative stress caused by overloading of Ca 2+ . As tetra‐sulfide bonds are sensitive to GSH, DMOS can generate hydrogen sulfide (H 2 S) gas as a new kind of H 2 S gas nanoreactor. Additionally, the overloading of Ca 2+ can cause tumor calcification to accelerate in vivo tumor necrosis and promote computed tomography imaging efficacy. Therefore, a novel H 2 S gas, EDT, and Ca 2+ ‐interference combined therapy strategy is developed.