A metal-free cascade nanoreactor reprograms the cystine-glutathione axis for disulfidptosis-pyroptosis therapy

Pyroptosis-based cancer therapy is often hindered by the overexpression of SLC7A11, which enhances glutathione (GSH) biosynthesis to maintain redox homeostasis and suppress pyroptotic cell death. To address this challenge, we developed a metal-free cascade nanoreactor (ITG@PCM) designed to disrupt redox balance via the cystine-GSH axis, thereby enabling synergistic disulfidptosis-pyroptosis therapy. This system employs an organic phase-change material (PCM) to co-encapsulate the photothermal agent IR825, copper chelator TPEN, and glucose oxidase (GOx), with on-demand payload release triggered by the thermal effect under 808 nm laser irradiation. Upon release, GOx catalyzes glucose oxidation, leading to nicotinamide adenine dinucleotide phosphate (NADPH) depletion and consequent actin cytoskeletal collapse, thereby inducing disulfidptosis through abnormal cystine accumulation via SLC7A11. Simultaneously, TPEN chelates Cu²⁺ from Cu-superoxide dismutase (Cu-SOD), forming Cu²⁺-TPEN complexes that abolish SOD activity and promote ·O₂^- accumulation due to impaired dismutation. Notably, Cu²⁺-TPEN is reduced by GSH to Cu⁺-TPEN, resulting in GSH depletion and catalyzing H₂O₂ into highly cytotoxic ·OH via a Fenton-like reaction. The combined effects of GSH depletion and cystine accumulation amplify oxidative stress, thereby activating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome/caspase-1/gasdermin D (GSDMD) signaling pathway to trigger pyroptosis. Collectively, this cascade-driven dual cell-death mechanism provides a promising paradigm for tumor therapy by precisely disrupting intracellular redox homeostasis. STATEMENT OF SIGNIFICANCE: This work presents a metal-free cascade nanoreactor (ITG@PCM) that strategically disrupts redox homeostasis to induce a synergistic disulfidptosis-pyroptosis anticancer response. By integrating a photothermal agent (IR825), a copper-selective chelator (TPEN), and glucose oxidase within a phase-change matrix, the system enables on-demand, laser-controlled release of therapeutics that simultaneously target the cystine-GSH axis and Cu/Zn-SOD. This dual intervention amplifies oxidative stress through cystine accumulation, GSH depletion, and catalytic hydroxyl radical (·OH) generation, thereby activating the NLRP3 inflammasome to trigger pyroptosis. The approach achieves potent antitumor efficacy without relying on transition-metal nanocatalysts, offering a safer alternative with high translational potential. Notably, this work also provides mechanistic insight into the interplay between disulfidptosis and pyroptosis and establishes a promising paradigm for redox-mediated cancer therapy.