GSH-Responsive Prodrug Polymersomes for Copper-Free Cuproptosis and Synergistic Photothermal Cancer Therapy

Cuproptosis offers a promising alternative to apoptosis-based cancer therapies but faces challenges, such as poor tumor drug accumulation, rapid clearance of copper ionophores, and high intracellular glutathione (GSH). Herein, we developed a GSH-responsive prodrug polymersome (PED@ICG) for copper-independent cuproptosis and synergistic photothermal therapy. Diethyldithiocarbamate (DTC) was covalently attached via disulfide bonds, ensuring a GSH-triggered release and intracellular GSH depletion. The amphiphilic polyprodrug formed stable polymersomes, and ICG coloading endowed imaging ability and NIR-activated photothermal heating. PED@ICG exhibited efficient cellular uptake through dynamin-mediated endocytosis, achieved deep tumor penetration, and selectively released DTC within the reductive tumor microenvironment. In vitro and in vivo studies demonstrated potent anticancer efficacy without the need for exogenous copper, while NIR irradiation further enhanced therapeutic outcomes through localized hyperthermia. This work offers a promising strategy for precise cuproptosis modulation and photothermal synergism, providing a clinically translatable nanoplatform for copper-independent tumor therapy.