An integrated ROS booster: Hydrogen sulfide-donating nanoclusters designed for multi-mode breast cancer treatment

Nanomaterial-assisted chemodynamic cancer therapy has received considerable attention in recent years. It outperforms other modalities for its unique pattern of reactive oxygen species (ROS) production via the non-exogenous stimulant. However, the treatment outcome is limited by the insufficient content of endogenous hydrogen peroxide (H2O2). Herein, a biodegradable H2S-releasing MnS@HA-DOX nanocluster (MnS@HA-DOX NC) was constructed by in situ biomineralization from hyaluronic acid, to amplify ROS cascade and boost Mn2+-based chemodynamic therapy (CDT). The acid-responsive NCs could quickly degrade after internalization into endo/lysosomes, releasing Mn2+, H2S gas, and anticancer drug doxorubicin (DOX). The Fenton-like reaction catalyzed by Mn2+ was amplified by both H2S and DOX, producing a mass of cytotoxic ·OH radicals. Through the combined action of gas therapy (GT), CDT, and chemotherapy, oxidative stress would be synergistically amplified, inducing irreversible DNA damage and cell cycle arrest, eventually resulting in cancer cell apoptosis.