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. <i>In vitro</i> and <i>in vivo</i> 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.