Charge and Size‐Variable Biodegradable Nanocomposites for Self‐Reinforcing CDT, PTT, and Chemotherapy: Augmented Cuproptosis and Ferroptosis against Tumor Hypoxia via Glycolysis/Redox Dual Disruption

Abstract Cuproptosis is a new type of regulated cell death with strong tumor‐suppressing potential; however, its effectiveness is often hindered by low copper levels, downregulated mitochondrial respiration, and high glutathione levels. Herein, a colorectal cancer (CRC) turn‐on nanocomposite (SHK/HCG@CuO ₂ /HA) is developed to achieve optimal synergistic augmentation of cuproptosis in conjunction with ferroptosis. SHK/HCG@CuO ₂ /HA decomposes in the acidic CRC tumor microenvironment, generating copper and H ₂ O ₂ . Simultaneously, releases shikonin (SHK), Glutathione (GSH)‐sensitive probe HCG, and copper can spontaneously assemble into positively charged nanoparticles (SHK/HCG@Cu) for facilitating deep tumor penetration. Following lysosomal rupture, SHK/HCG@Cu disintegrates due to excess GSH, releasing copper that reacts with H ₂ S to form CuSx nanocrystals with effective NIR absorption for precise photothermal therapy (PTT) efficiency. More importantly, red fluorescence activation in HCG by GSH facilitates real‐time self‐reporting of irradiation duration during PTT. Notably, loaded SHK eliciting an anti‐Warburg effect, reprograms the energy metabolic system from glycolysis to mitochondrial respiration, contributing to cuproptosis sensitization. Additionally, high ROS production from the Fenton reaction in chemodynamic therapy (CDT) triggers apoptosis and increases lipid peroxide (LPO) accumulation, causing ferroptosis in tumor cells. Consequently, SHK/HCG@CuO ₂ /HA exhibits efficient intratumoral accumulation and penetration via a charge/size‐variable mechanism along with spatial cooperativity in glycolysis inhibition‐enhanced cuproptosis and ferroptosis, realizing enhanced CDT, PTT, and chemotherapy.