Self‐Propagating Acid Avalanche Unleashes Endogenous Iron to Fuel Potentiated Chemodynamic Therapy

The therapeutic efficacy of chemodynamic therapy (CDT) is intrinsically compromised by the mildly acidic tumor microenvironment (TME), which fails to satisfy the stringent pH demands required to mobilize endogenous iron for sustainable Fenton reactions. Herein, we propose a self‐propagating “acid avalanche” strategy using CD44‐targeting USGND@HMCS (i.e., ultrasmall gold nanodots‐anchored 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 2 S, triggering a triaxial acidification cascade: (i) USGND‐catalyzed conversion of glucose to gluconic acid and hydrogen peroxide (H 2 O 2 ); (ii) H 2 S‐mediated 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‐supplied H 2 O 2 to drive a self‐amplifying 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 “acid‐driven iron mobilization” strategy achieves significant growth suppression, offering a robust paradigm for enhanced CDT.