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Herein, we propose a self\u2010propagating \u201cacid avalanche\u201d strategy using CD44\u2010targeting USGND@HMCS (i.e., ultrasmall gold nanodots\u2010anchored hollow mesoporous copper sulfide) nanoreactors to hijack organelle homeostasis and unleash intracellular iron depots for catastrophic tumor destruction. Upon accumulation in TME, the nanoreactors degrade to release USGND, copper ions, and H\n                    <jats:sub>2<\/jats:sub>\n                    S, triggering a triaxial acidification cascade: (i) USGND\u2010catalyzed conversion of glucose to gluconic acid and hydrogen peroxide (H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    ); (ii) H\n                    <jats:sub>2<\/jats:sub>\n                    S\u2010mediated mitochondrial respiration inhibition, leading to compensatory lactate accumulation; (iii) lysosomal proton leakage via membrane permeabilization. The coordinated surge in intracellular acidity and organelle dysfunction mobilizes the endogenous iron pool, which synergizes with released Cu ions and self\u2010supplied H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    to drive a self\u2010amplifying oxidative storm that culminates in potent ferroptotic cell death. Notably, the heightened acidity creates a positive feedback loop by accelerating nanoreactor degradation, thereby overcoming the kinetic inertness of CDT in TME. Both in vitro and in vivo evaluations validate that our \u201cacid\u2010driven iron mobilization\u201d strategy achieves significant growth suppression, offering a robust paradigm for enhanced CDT.\n                  <\/jats:p>","DOI":"10.1002\/smll.74492","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T10:27:53Z","timestamp":1783506473000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Self\u2010Propagating Acid Avalanche Unleashes Endogenous Iron to Fuel Potentiated Chemodynamic Therapy"],"prefix":"10.1002","volume":"22","author":[{"given":"Dingshang","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Medical Imaging The Third Affiliated Hospital Southern Medical University (Academy of Orthopedics\u00b7Guangdong Province)  Guangzhou Guangdong 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