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

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 (H₂ O₂ ) 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 (CaO₂ -HA NPs). The nanocomposite can effectively generate singlet oxygen (¹ O₂ ) for tumor therapy without any exogenous stimulus via trimodal-enhanced EDT, including DMOS-induced depletion of glutathione (GSH), H₂ O₂ compensation from CaO₂ -HA NPs in mildly acidic TME, and oxidative stress caused by overloading of Ca²⁺ . As tetra-sulfide bonds are sensitive to GSH, DMOS can generate hydrogen sulfide (H₂ S) gas as a new kind of H₂ S gas nanoreactor. Additionally, the overloading of Ca²⁺ can cause tumor calcification to accelerate in vivo tumor necrosis and promote computed tomography imaging efficacy. Therefore, a novel H₂ S gas, EDT, and Ca²⁺ -interference combined therapy strategy is developed.