Engineered Stem Cell Membrane-Coated Nanodrugs for Targeted Therapy of Alzheimer's Disease.

The pathological complexity of Alzheimer's disease (AD) necessitates the development of efficient nanomedicine delivery systems. Nanoparticles are considered promising therapeutic candidates for AD owing to their drug-loading capacity. This study introduces an engineered cell membrane coating strategy to enhance nanoparticle functionality in targeting efficiency and susceptivity to immune clearance. We developed an engineered biomimetic nanodrug delivery system by modifying nanoparticles with Gas6-overexpressing neural stem cell membranes for improving microglia targeting, pro-phagocytic properties and immunomodulatory effects, constructing a composite system designated as Gas6-NV-NPs. The system employs poly(lactic-co-glycolic acid) (PLGA) as a carrier to coencapsulate Rapamycin (RAP) and nicotinamide riboside (NR) (referred to as NPs), while leveraging Gas6 protein to specifically bind microglial surface receptors, enabling precise targeting of AD pathological regions. Our findings demonstrated that Gas6-NV-NPs restored lysosomal acidification in microglia, enhanced microglial phagocytic clearance of amyloid-β (Aβ), and reinstated the anti-inflammatory phenotype in BV2 microglial cells. Furthermore, Gas6-NV-NPs exhibited favorable biosafety and robust brain-targeting capability in vivo, effectively promoting Aβ clearance and neuronal repair in 5 × FAD mice model of AD. This "engineered membrane modification-nanodrug delivery" synergistic strategy enhances therapeutic targeting and achieves multitargeted effects, offering a approach to overcoming critical bottlenecks in AD nanotherapy.