A Self‐Reinforced “Microglia Energy Modulator” for Synergistic Amyloid‐β Clearance in Alzheimer's Disease Model

Abstract Microglial phagocytosis is a highly energy‐consuming process that plays critical roles in clearing neurotoxic amyloid‐β (Aβ) in Alzheimer's disease (AD). However, microglial metabolism is defective overall in AD, thereby undermining microglial phagocytic functions. Herein, we repurpose the existing antineoplastic drug lonidamine (LND) conjugated with hollow mesoporous Prussian blue (HMPB) as a “microglial energy modulator” (termed LND@HMPB‐T7) for safe and synergistic Aβ clearance. The modified blood–brain barrier penetrating heptapeptide (T7) enables efficient transport of LND@HMPB‐T7 to the AD brain. LND in LND@HMPB‐T7 could fuel Aβ phagocytosis by stimulating microglial adenosine triphosphate (ATP) production, whereas HMPB with catalase and superoxide dismutase‐mimicking activities substantially alleviates the mitochondrial side effects commonly associated with LND and thus further enhances ATP production. The synergism of LND and nanozyme affords a high microglial Aβ clearance efficacy without triggering mitochondrial dysfunction. In vivo experiments ascertain that LND@HMPB‐T7 could synergistically promote phagocytic clearance of Aβ, relieve neuroinflammation and ameliorate cognitive function in AD mice. These findings indicate that LND@HMPB‐T7 holds tremendous clinical potential as a repurposed drug for AD treatment.