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.

Recent advances in upconversion nanoparticle-based nanocomposites for gas therapy

“…H 2 S induces cytoprotection and anti-inflammatory effects at relatively lower concentrations, and leads to mitochondrial inhibition and cell death (activation of caspase 9 and apoptosis 161) at higher concentrations. 22,40,96 A simple NIR light-induced H 2 S generation nanoplatform based on UCNPs was constructed (Fig. 6a).…”

A Potent Strategy of Combinational Blow Toward Enhanced Cancer Chemo‐Photodynamic Therapy via Sustainable GSH Elimination

“…This inhibition leads to a dilemma on the use of multimodal therapy, which has already demonstrated a superadditive effect for cancer treatment. [ 12–20 ] Currently, stunning GSH depletion strategies that are used in combination with cancer therapy are mainly focused on the direct elimination of GSH [ 4,21–28 ] or on the elimination of its upstream molecules, such as L‐cysteine, which are required for the synthesis of GSH. [ 1,29 ] Various enzyme inhibitors efficiently block the generation of intracellular GSH.…”

“…This inhibition leads to a dilemma on the use of multimodal therapy, which has already demonstrated a superadditive effect for cancer treatment. [12][13][14][15][16][17][18][19][20] Currently, stunning GSH depletion strategies that are used in combination with cancer therapy are mainly focused on the direct elimination of GSH [4,[21][22][23][24][25][26][27][28] or on the elimination of its upstream molecules, such as L-cysteine, which are required for the synthesis of GSH. [1,29] Various enzyme inhibitors efficiently block Excessive glutathione (GSH), which is produced owing to abnormal metabolism of tumor cells, scavenges photo-induced reactive oxygen species (ROS) and consumes chemotherapeutic drugs, thereby attenuating the efficacy of photodynamic therapy and chemotherapy, respectively.…”

“Four‐in‐One” Nanozyme and Natural Enzyme Symbiotic System of Cu2‐xSe−GOx for Cervical Cancer Therapy

“…[15] Subsequently, a large number of nanozymes were developed and applied in different fields. [16] In recent years, TME-activated enzyme dynamic therapy, [17] as a burgeoning reactive oxygen species (ROS)-based dynamic therapy model, [18] has attracted extensive attention. [19] Natural enzymes in living organisms are proteins composed of several hundred amino acids, [20] which have quite high catalytic activity and substrate specificity.…”