A Tumor‐Microenvironment‐Responsive Nanocomposite for Hydrogen Sulfide Gas and Trimodal‐Enhanced Enzyme Dynamic Therapy
Bin Liu, Shuang Liang, Zhao Wang, Qianqian Sun, Fei He, Shili Gai, Piaoping Yang, Ziyong Cheng, Jun Lin
Abstract
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.