Integrating a Biomineralized Nanocluster for HS-Sensitized ROS Bomb against Breast Cancer.

Nanomaterial-assisted chemodynamic therapy (CDT) has received considerable attention in recent years. It outperforms other modalities by its distinctive reactive oxygen species (ROS) generation through a nonexogenous stimulant. However, CDT is limited by the insufficient content of endogenous hydrogen peroxide (HO). Herein, a biodegradable MnS@HA-DOX nanocluster (MnS@HA-DOX NC) was constructed by biomineralization from hyaluronic acid, to enlarge the ROS cascade and boost Mn-based CDT. The acid-responsive NCs could quickly degrade after internalization into endo/lysosomes, releasing Mn, HS gas, and anticancer drug doxorubicin (DOX). The Fenton-like reaction catalyzed by Mn was amplified by both HS 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 enhanced, inducing irreversible DNA damage and cell cycle arrest, eventually resulting in cancer cell apoptosis.