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Herein, a porous Fe\n                    <jats:sub>3<\/jats:sub>\n                    O\n                    <jats:sub>4<\/jats:sub>\n                    nanoplatform is engineered through coating of Fe\n                    <jats:sup>3<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    \u2010tannic acid complex onto nanoclusters simultaneously loaded with carbonyl cyanide 3\u2010chlorophenylhydrazone (CCCP, a mitochondrial uncoupler) and lactate oxidase (LOD). By self\u2010supplying H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    and concurrently blocking autophagic flux, this system is engineered to potentiate CDT efficacy. Beyond the expected therapeutic outcome, we uncover that this nanoplatform triggers an unconventional cell death pathway\u2014paraptosis. Acid\u2010triggered dissociation in the tumor microenvironment releases Fe\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    \/Fe\n                    <jats:sup>3<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    for Fenton reactions while LOD simultaneously converts lactate to H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    , overcoming the H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    bottleneck. CCCP further synergizes this process by collapsing the mitochondrial membrane potential, which amplifies ROS leakage and culminates in an oxidative storm. This dramatic surge in ROS directly induces mitochondrial dysfunction and initiates endoplasmic reticulum stress, while also suppressing autophagic flux. Collectively, these multi\u2010organelle stresses markedly exacerbate intracellular damage and lead to paraptotic cell death, characterized by extensive cytoplasmic vacuolization, eliciting robust immunogenic cell death. Combined with \u03b1PD\u2010L1, the nanoplatform potently activates antitumor immunity and suppresses both primary and distant tumors. This work pioneers a paraptosis activation strategy driven by an iron\u2010based nanodrug, redefining CDT efficacy through multi\u2010organelle stress synergy for amplified immunotherapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520031","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T09:44:15Z","timestamp":1772963055000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Multi\u2010Organelle Stress\u2010Induced Paraptosis by a ROS\u2010Amplifying Nanocatalyst for Enhanced Cancer Immunotherapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhe","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Analysis School of Pharmacy The Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haozhe","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Stomatology Lanzhou University  Lanzhou China"},{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Diseases Shaanxi Key Laboratory of Stomatology School of Stomatology The Fourth Military Medical University  Xi'an China"},{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, School of Stomatology The Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chinese Materia Medica and Natural Medicines School of Pharmacy The Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis 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