Endocytosed pH‐Sensitive Nanoparticles Orchestrate Mitochondrial Bioenergetics and Calcium Signaling to Boost NSC‐Mediated Alzheimer's Therapy

ABSTRACT Neural stem cell (NSC) transplantation holds great potential for Alzheimer's disease (AD) therapy; however, its efficacy is severely compromised by the oxidative microenvironment, which impairs mitochondrial function and promotes aberrant glial differentiation. To overcome this barrier, lysosome‐responsive EGCG–lysine nanoparticles (EL NPs) were developed. Upon endo‐lysosomal disassembly, EL NPs release active components that scavenge reactive oxygen species (ROS) and restore mitochondrial bioenergetics via AMPK signaling. This metabolic rescue activates a Ca 2 + ‐dependent MAPK pathway, driving commitment to the GABAergic neuronal lineage. Under oxidative stress, EL NPs enhanced neuronal differentiation efficiency by 2.5–3.0‐fold compared with spontaneous differentiation while suppressing astroglial activation. In an AD mouse model, transplantation of EL NP‐loaded NSCs promoted in situ neurogenesis, attenuated neuroinflammation, and restored cognitive performance to ∼89%–90% of wild‐type levels. These results present a translatable strategy to augment NSC‐based repair by modulating intracellular responses to oxidative stress and promoting neuronal differentiation.