Mitochondrial dysfunction has been recognized as the key pathogenesis of most neurodegenerative diseases including Alzheimer's disease (AD). The dysregulation of mitochondrial calcium ion (Ca2+) homeostasis and the mitochondrial permeability transition pore (mPTP), is a critical upstream signaling pathway that contributes to the mitochondrial dysfunction cascade in AD pathogenesis. Herein, a “two‐hit braking” therapeutic strategy to synergistically halt mitochondrial Ca2+ overload and mPTP opening to put the mitochondrial dysfunction cascade on a brake is proposed. To achieve this goal, magnesium ion (Mg2+), a natural Ca2+ antagonist, and siRNA to the central mPTP regulator cyclophilin D (CypD), are co‐encapsulated into the designed nano‐brake; A matrix metalloproteinase 9 (MMP9) activatable cell‐penetrating peptide (MAP) is anchored on the surface of nano‐brake to overcome the blood‐brain barrier (BBB) and realize targeted delivery to the mitochondrial dysfunction cells of the brain. Nano‐brake treatment efficiently halts the mitochondrial dysfunction cascade in the cerebrovascular endothelial cells, neurons, and microglia and powerfully alleviates AD neuropathology and rescues cognitive deficits. These findings collectively demonstrate the potential of advanced design of nanotherapeutics to halt the key upstream signaling pathways of mitochondrial dysfunction to provide a powerful strategy for AD modifying therapy.

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