Ultrasound-Guided Mobilization of Dual Autophagic Cleaning Crew by Exosomal Rapamycin Ameliorates the Progression of Parkinsonism.
5 affiliations
- 1Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China.
- 2Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, People's Republic of China.
- 3Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, 710062, People's Republic of China.
- 4Key Laboratory of Biomedical Information Engineering of Ministry of Education and Department of Biomedical Engineering School of Life Science and Technology Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China.
- 5State Key Laboratory for Manufacturing Systems Engineering, School of Mechanical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, People's Republic of China.
Abstract
Autophagy dysfunction is a key contributor to Parkinson's disease (PD) pathogenesis, driving α-synuclein (α-syn) accumulation and progressive dopaminergic neurodegeneration. Although enhancing autophagic clearance of α-syn represents a promising therapeutic strategy, achieving controlled modulation of autophagic flux while maintaining neuronal viability remains challenging. A focused ultrasound (FUS)-enabled exosomal rapamycin delivery platform (EXO-RPM) was designed to modulate autophagic degradation in PD models. We systematically characterized their morphology, physicochemical properties, and environmental stability. In vitro studies assessed cellular uptake, cytotoxicity, autophagy induction, autophagic pathway modulation, and α-syn clearance. Subsequently, ultrasound-guided brain accumulation, behavioral recovery, brain immunofluorescence, and positron emission tomography (PET) imaging were evaluated in vivo. Finally, the biosafety of the nanoplatform was evaluated via histopathological and biochemical analyses. Under optimized conditions, EXO-RPM achieved a high encapsulation efficiency of 90.14%. This platform exploits endogenous transferrin-transferrin receptor interactions for brain-targeted delivery, while FUS provides spatiotemporal control by transiently opening the blood-brain barrier (BBB) and thereby enhancing drug accumulation in the brain parenchyma. Following FUS-mediated delivery, EXO-RPM reduced α-syn aggregation and neuronal toxicity in parkinsonian models. Mechanistically, EXO-RPM treatment activated both macroautophagy and chaperone-mediated autophagy (CMA)-related pathways, thereby promoting autophagic degradation of pathological α-syn. These effects were accompanied by increased striatal dopamine levels and elevated [18F]FP-(+)-DTBZ uptake in VMAT2-positive synaptic vesicles, as revealed by PET, ultimately ameliorating MPTP-induced motor deficits in parkinsonian mice. These findings suggest that FUS-enabled exosomal delivery may provide a strategy for restoring autophagic homeostasis and mitigating α-syn-driven neurodegeneration, with potential relevance to PD and other protein aggregation-associated central nervous system (CNS) disorders.
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BibTeX
@article{liu2026ultrasoundguided,
title = {{Ultrasound-Guided Mobilization of Dual Autophagic Cleaning Crew by Exosomal Rapamycin Ameliorates the Progression of Parkinsonism.}},
author = {Yichen Liu and Kaili Guo and Xin Li and Yan Li and Xiaoming Zheng and Pan Wang},
journal = {International journal of nanomedicine},
year = {2026},
month = oct,
doi = {10.2147/ijn.s625730},
url = {https://europepmc.org/article/MED/42953137},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Ultrasound-Guided Mobilization of Dual Autophagic Cleaning Crew by Exosomal Rapamycin Ameliorates the Progression of Parkinsonism.
AU - Yichen Liu
AU - Kaili Guo
AU - Xin Li
AU - Yan Li
AU - Xiaoming Zheng
AU - Pan Wang
PY - 2026
DA - 2026/10/25
JO - International journal of nanomedicine
DO - 10.2147/ijn.s625730
UR - https://europepmc.org/article/MED/42953137
AB - Autophagy dysfunction is a key contributor to Parkinson's disease (PD) pathogenesis, driving α-synuclein (α-syn) accumulation and progressive dopaminergic neurodegeneration. Although enhancing autophagic clearance of α-syn represents a promising therapeutic strategy, achieving controlled modulation of autophagic flux while maintaining neuronal viability remains challenging. A focused ultrasound (FUS)-enabled exosomal rapamycin delivery platform (EXO-RPM) was designed to modulate autophagic degradation in PD models. We systematically characterized their morphology, physicochemical properties, and environmental stability. In vitro studies assessed cellular uptake, cytotoxicity, autophagy induction, autophagic pathway modulation, and α-syn clearance. Subsequently, ultrasound-guided brain accumulation, behavioral recovery, brain immunofluorescence, and positron emission tomography (PET) imaging were evaluated in vivo. Finally, the biosafety of the nanoplatform was evaluated via histopathological and biochemical analyses. Under optimized conditions, EXO-RPM achieved a high encapsulation efficiency of 90.14%. This platform exploits endogenous transferrin-transferrin receptor interactions for brain-targeted delivery, while FUS provides spatiotemporal control by transiently opening the blood-brain barrier (BBB) and thereby enhancing drug accumulation in the brain parenchyma. Following FUS-mediated delivery, EXO-RPM reduced α-syn aggregation and neuronal toxicity in parkinsonian models. Mechanistically, EXO-RPM treatment activated both macroautophagy and chaperone-mediated autophagy (CMA)-related pathways, thereby promoting autophagic degradation of pathological α-syn. These effects were accompanied by increased striatal dopamine levels and elevated [18F]FP-(+)-DTBZ uptake in VMAT2-positive synaptic vesicles, as revealed by PET, ultimately ameliorating MPTP-induced motor deficits in parkinsonian mice. These findings suggest that FUS-enabled exosomal delivery may provide a strategy for restoring autophagic homeostasis and mitigating α-syn-driven neurodegeneration, with potential relevance to PD and other protein aggregation-associated central nervous system (CNS) disorders.
SN - 1176-9114
SN - 1178-2013
ER -