Oxygen pump microneedles coupling cuproptosis and disulfidptosis to enhance melanoma immunotherapy

An oxygen-pump microneedle system is developed for deep drug penetration and hypoxia alleviation. • Synergistic cuproptosis and disulfidptosis are achieved via a MIRV-inspired strategy. • GOx-mediated GSH depletion sensitizes cuproptosis and triggers disulfidptosis. • The system triggers robust antitumor immunity and inhibits melanoma growth and lung metastasis. Cuproptosis and disulfidptosis are new types of programmed cell death with great potential for tumor immunotherapy, but their efficacy is severely restricted by the hypoxic microenvironment and metabolic reprogramming of tumors. Herein, we develop an oxygen-pump microneedle system (CPGH@OMN) co -loading glucose oxidase (GOx) and copper-polyphenol nanoparticles (CP), using sodium percarbonate (SPC) as an in situ oxygen generator and hyaluronic acid (HA) as a tumor-targeting carrier. SPC-mediated oxygen generation acts as a booster to promote deep drug penetration, and downregulates hypoxia-inducible factor-1α (HIF-1α) to alleviate tumor hypoxia. GOx depletes glucose and nicotinamide adenine dinucleotide phosphate (NADPH) to trigger disulfidptosis, which consumes glutathione (GSH) to sensitize cuproptosis. Copper ions from CPGH (CP-GOx-HA) induce robust cuproptosis under the favorable conditions of downregulated HIF-1α and GSH. The suppression of metabolic reprogramming in tumor cells by alleviating hypoxia and depleting NADPH and GSH significantly enhances anti-tumor immune responses. Animal experiment results demonstrate that CPGH@OMN significantly inhibits orthotopic tumor growth and lung metastasis. This oxygen-pump microneedle strategy integrating physical penetration enhancement and metabolic reprogramming provides a novel approach for melanoma immunotherapy. An oxygen-pump microneedle system (CPGH@OMN) inspired by the multiple independently targetable reentry vehicle (MIRV) strategy is developed to improve melanoma immunotherapy. In situ oxygen generation acts as a “booster” to boost deep drug penetration and relieve tumor hypoxia, while glucose oxidase and copper ions acts as “sub-warhead” to promote disulfidptosis and cuproptosis. CPGH@OMN effectively inhibits orthotopic melanoma growth and lung metastasis by enhancing immunogenic cell death. Download: Download high-res image (146KB) Download: Download full-size image