ROS-responsive oligochitosan-derived nanovesicles with synergistic oxidative stress and autophagy inhibition for potent tumor therapy.

Oxidative stress-mediated tumor therapy leverages reactive oxygen species (ROS) for cancer treatment, but protective autophagy, a major survival pathway for tumor cells, causes therapy resistance. Herein, a self-amplifying ROS-responsive nanovesicle system (CQ/Cu@CT) is designed to enhance oxidative stress while blocking autophagy. Firstly, amphiphilic oligochitosan derivative COS-PEG2KTA-UB is synthesized, where ROS-responsive thioketal acetal (TA) is introduced in form of cinnamaldehyde (CA) prodrug. This polymer self-assembles into nanovesicles, integrating chloroquine (CQ) and supplemental TA to immobilize Cu2+ via carboxylic coordination. Intracellular ROS triggers nanovesicle dissociation to release CA, Cu2+, and CQ. CA induces mitochondrial dysfunction and ROS burst, while Cu2+ depletes glutathione and generates Cu+ for Fenton-like reactions to produce hydroxyl radicals. Meanwhile, due to the inhibition effect of CQ on protective autophagy, CQ/Cu@CT produces significantly high ROS level. The amplified ROS not only aggravates oxidative stress but also accelerates drug release from nanovesicles, which facilitates the drug action against tumors. CQ/Cu@CT also induces immunogenic cell death (ICD) to stimulate dendritic cell maturation and enhance cytotoxic T lymphocyte infiltration. Consequently, CQ/Cu@CT inhibits tumor growth by 67.8 % in a subcutaneous 4 T1 tumor model. This study provides a potent strategy to enhance oxidative stress-based cancer therapy.