biostudies-literatureLi MNational Natural Science Foundation of China (National Science Foundation of China)360https://www.ebi.ac.uk/biostudies/studies/S-EPMC12583606biostudies-literatureUnknown10(1)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, thSignal transduction and targeted therapyMicroglia-derived nanovesicles synchronize macroautophagy and chaperone-mediated autophagy for Alzheimer's disease therapy.PMC12583606NSFC-STINT 82311530116Liu YLi JWang BYang MChen FChen SGuo RWang YHe QLi MZhang QZhu SfalseMicroglia-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, th2025-01-01T00:00:00Z2025 Nov2026-06-05T11:36:49.605Z2026-05-16T03:11:57.294ZS-EPMC125836064118427110.1038/s41392-025-02453-y