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 (H2O2) 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 (O-1(2)) for tumor therapy without any exogenous stimulus via trimodal-enhanced EDT, including DMOS-induced depletion of glutathione (GSH), H2O2 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 (H2S) gas as a new kind of H2S 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 H2S gas, EDT, and Ca2+-interference combined therapy strategy is developed.

Automated summary

A rapidly decomposing nanocomposite was designed in this study to improve the efficiency of enzyme dynamic therapy, enhancing tumor therapy through multiple pathways and developing a new treatment strategy.