Microglia-derived nanovesicles synchronize macroautophagy and chaperone-mediated autophagy for Alzheimer's disease therapy.

Dysregulated autophagy is a hallmark of Alzheimer's disease (AD), yet the extent of impairment in macroautophagy and chaperone-mediated autophagy (CMA) remains unclear. Here, we show that both pathways are disrupted in AD model mice, preceding β-amyloid accumulation and driving disease progression. However, therapeutic autophagy modulation is severely restricted by the blood-brain barrier (BBB). To overcome this, we developed Microglia-Liposome Fusion Extrusion (MiLi-FE), a method to engineer microglia-derived nanovesicles (AR@ENV) for the codelivery of AR7 (a CMA inducer) and rapamycin (a macroautophagy inducer). Leveraging its microglial membrane origin, AR@ENV effectively crosses the BBB and targets inflammatory sites in the AD brain, where it is internalized by neurons. Once inside, they synchronously activate both autophagy pathways: AR7 antagonizes retinoic acid receptor alpha (RARα) to enhance CMA, while rapamycin inhibits mTOR to promote macroautophagy. This coordinated activation enhances clearance of β-amyloid and other toxic aggregates, restores proteostasis, and provides robust neuroprotection. Furthermore, the strategy ameliorates neuroinflammation and significantly rescues cognitive deficits in two distinct AD mouse models. By integrating synchronized dual autophagy activation with targeted biomimetic delivery, AR@ENV represents a promising therapeutic candidate for AD. Moreover, the MiLi-FE platform offers a versatile and scalable approach for delivering diverse therapeutics to the central nervous system, extending its potential applicability to a range of neurological disorders.