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Herein, tumor\u2010targeting and GSH self\u2010depleting hyaluronic acid (HA)\/tannic acid (TA)\u2010engineered Prussian blue (PB) oxygen nanogenerators (ONs) loaded with IR780 (IHTPB ONs) are developed to enhance synergistic PTT\/PDT. The IHTPB ONs exhibit uniform morphology, excellent colloidal stability, acidity\/GSH\u2010responsive IR780 release, high photothermal conversion efficiency (60%), and outstanding photothermal stability. Importantly, PB\u2010mediated GSH oxidation and TA\u2010mediated GSH conjugation enable dual\u2010mode GSH depletion, while PB catalyzes oxygen generation to alleviate tumor hypoxia and promote IR780\u2010mediated singlet oxygen production. Following CD44\u2010mediated cellular uptake, IHTPB ONs effectively deplete intracellular GSH and, under near\u2010infrared irradiation, induce robust reactive oxygen species generation and hyperthermia, leading to mitochondrial dysfunction, lipid peroxidation, apoptosis, and ferroptosis. In vivo, IHTPB ONs exhibit superior tumor accumulation and significantly enhanced antitumor efficacy compared with free IR780 and non\u2010targeted nanoparticles, resulting in prolonged survival of melanoma\u2010bearing mice. This work provides an effective nanoplatform integrating tumor targeting, oxygen self\u2010supply, and dual\u2010mode GSH depletion to potentiate synergistic PTT\/PDT for melanoma therapy.<\/jats:p>","DOI":"10.1002\/adhm.71596","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:25:35Z","timestamp":1787027135000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor\u2010Targeted Hyaluronic Acid\/Tannic Acid\u2010Engineered Oxygen Nanogenerators With IR780 Payloads Enable Dual\u2010Mode Glutathione Depletion and Effective Singlet Oxygen Generation for Melanoma Treatment"],"prefix":"10.1002","volume":"15","author":[{"given":"Chai\u2010How","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering National Chung Hsing University  Taichung 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