Lysosomal membrane damage repair and acidification impairment restoration triggered by smart lipid nanoparticles for Alzheimer's disease treatment.
4 affiliations
- 1The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center of Nanjing Medical University; Pharmacy School of Nanjing Medical University, Nanjing 211166, China.
- 2Jiangsu Province Innovation Center for Brain-Inspired Intelligence Technology, Nanjing 210000, China.
- 3Department of Pharmacy, The Affiliated Jiangyin Clinical College of Xuzhou Medical University, Jiangyin 214400, China.
- 4School of Basic Medical Sciences Nanjing Medical University, Nanjing 211166, China.
Abstract
Alzheimer's disease (AD), characterized by amyloid (Aβ) deposition in neurons, is the most serious neurodegenerative disorder, but lacks effective therapeutic drugs in the clinic. Impaired neuronal lysosomal function drives the pathological accumulation of intracellular Aβ. Targeted rehabilitation of lysosomal dysfunction may offer a potential strategy to restore neuronal homeostasis and mitigate AD progression. In this study, we developed a brain-targeted smart lipid nanoparticle (A-PSL@7BIO) to repair lysosomal membrane damage and restore impaired acidification in the brain for AD therapy. The system was composed of Angiopep-2 peptide-conjugated lipid nanoparticles, which were loaded with a Glycogen synthase kinase-3β (GSK-3β) inhibitor 7-bromoindirubin-3'-oxime (7BIO) and incorporated with dipalmitoyl-phosphatidylserine (DPPS) and a reactive oxygen species (ROS) responsive phospholipid. Through Angiopep-2-mediated blood-brain barrier (BBB) transcytosis, the smart lipid nanoparticles could enhance brain biodistribution with subsequent neuronal internalization. Pathologically elevated intracellular ROS levels in AD could induce stimulus-responsive payload release, wherein 7BIO selectively inhibited aberrant GSK-3β hyperphosphorylation to restore the physiological acidic lysosomal environment and DPPS structurally repaired compromised lysosomal membranes, synergistically addressing dual aspects of lysosomal pathology. This smart lipid nanoparticles synergistically restored physiological lysosomal homeostasis, reversed neuronal dysfunction, and ameliorated cognitive deficits in AD models, indicating that A-PSL@7BIO could be used as a potential nanomedicine for AD therapy.
Related
- Combined lactate- and phosphate-dependent cytoplasmic acidification is associated with Mycobacterium tuberculosis growth arrest at acidic pH
- Macroscopic two-dimensional sheets by chemically triggered self-assembly.
- A premature ovarian insufficiency-associated LMD-3 point mutation impairs protein stability and causes autophagic-lysosomal dysfunction in Caenorhabditis elegans
- Solvent-coordination-triggered framework breathing enables rapid polychlorinated biphenyls elution from magnetic Fe3O4/MIL-88B(Fe) composites
- Trace H2O2-triggered Fenton-like reaction by secondary coordination sphere in iron-based metal-organic frameworks
BibTeX
@article{yin2026lysosomal,
title = {{Lysosomal membrane damage repair and acidification impairment restoration triggered by smart lipid nanoparticles for Alzheimer's disease treatment.}},
author = {Jiaqing Yin and Wei Lv and Wei Zhao and Zhenwei Ding and Fei Zhu and Hongli Liu and Shengnan Li and Xiang Cao and Linfeng Liu and Kefan Song and Yue Gong and Jiangna Xu and Yuqin Chen and Zhiyuan Zhang and Xiangming Fang and Hongliang Xin},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = jun,
doi = {10.1016/j.apsb.2026.06.036},
url = {https://europepmc.org/article/MED/42948702},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Lysosomal membrane damage repair and acidification impairment restoration triggered by smart lipid nanoparticles for Alzheimer's disease treatment.
AU - Jiaqing Yin
AU - Wei Lv
AU - Wei Zhao
AU - Zhenwei Ding
AU - Fei Zhu
AU - Hongli Liu
AU - Shengnan Li
AU - Xiang Cao
AU - Linfeng Liu
AU - Kefan Song
AU - Yue Gong
AU - Jiangna Xu
AU - Yuqin Chen
AU - Zhiyuan Zhang
AU - Xiangming Fang
AU - Hongliang Xin
PY - 2026
DA - 2026/06/22
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.06.036
UR - https://europepmc.org/article/MED/42948702
AB - Alzheimer's disease (AD), characterized by amyloid (Aβ) deposition in neurons, is the most serious neurodegenerative disorder, but lacks effective therapeutic drugs in the clinic. Impaired neuronal lysosomal function drives the pathological accumulation of intracellular Aβ. Targeted rehabilitation of lysosomal dysfunction may offer a potential strategy to restore neuronal homeostasis and mitigate AD progression. In this study, we developed a brain-targeted smart lipid nanoparticle (A-PSL@7BIO) to repair lysosomal membrane damage and restore impaired acidification in the brain for AD therapy. The system was composed of Angiopep-2 peptide-conjugated lipid nanoparticles, which were loaded with a Glycogen synthase kinase-3β (GSK-3β) inhibitor 7-bromoindirubin-3'-oxime (7BIO) and incorporated with dipalmitoyl-phosphatidylserine (DPPS) and a reactive oxygen species (ROS) responsive phospholipid. Through Angiopep-2-mediated blood-brain barrier (BBB) transcytosis, the smart lipid nanoparticles could enhance brain biodistribution with subsequent neuronal internalization. Pathologically elevated intracellular ROS levels in AD could induce stimulus-responsive payload release, wherein 7BIO selectively inhibited aberrant GSK-3β hyperphosphorylation to restore the physiological acidic lysosomal environment and DPPS structurally repaired compromised lysosomal membranes, synergistically addressing dual aspects of lysosomal pathology. This smart lipid nanoparticles synergistically restored physiological lysosomal homeostasis, reversed neuronal dysfunction, and ameliorated cognitive deficits in AD models, indicating that A-PSL@7BIO could be used as a potential nanomedicine for AD therapy.
SN - 2211-3835
SN - 2211-3843
ER -