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

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

  • Signal Transduct Target Ther. 2025 Nov 3;10(1):360. doi: 10.1038/s41392-025-02453-y.
Min Li 1,  Shuang Chen 1,  Rong Guo 2,  Yang Wang 1 3,  Mingrui Yang 1,  Yingke Liu 4,  Qiang Zhang 1,  Shiyu Zhu 1,  Jiaxin Li 1,  Fang Chen 1,  Bo Wang 1,  Man Li 5,  Qin He 6
Affiliations

Affiliations

  • 1 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, PR China.
  • 2 Department of Biochemistry and Molecular Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China.
  • 3 Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
  • 4 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China.
  • 5 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, PR China. [email protected].
  • 6 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, PR China. [email protected].
PMID: 41184271 DOI: 10.1038/s41392-025-02453-y
Abstract

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.

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