Advanced healthcare materialsApr 25, 2026

Nanoparticles That Acidify Cell Recycling Compartments Reduce Neuron Death Caused by A30P α-Synuclein in Cell and Fruit Fly Models of Parkinson's Disease

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Updated Apr 26, 2026

Abstract

Over 10 million people worldwide are affected by Parkinson's disease (PD), which involves the accumulation of misfolded α-synuclein in neurons.

α-Synuclein accumulation is linked to impaired lysosomal acidification and defective autophagy-lysosomal degradation.
Lysosome-targeted acidic nanoparticles (AcNPs) were engineered to locally acidify impaired lysosomes and restore their function.
In vitro studies showed AcNPs restored lysosomal pH, enhanced the clearance of α-synuclein, and improved mitochondrial function.
In vivo treatment with AcNPs reduced α-synuclein burden, preserved dopaminergic neurons, and improved motor function in fruit flies.
The findings indicate potential therapeutic applications of pH-modulating nanomaterials for Parkinson's disease and related neurodegenerative disorders.

Simplified

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting over 10 million people worldwide. It is characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the accumulation of misfolded α-synuclein (αSyn) in intracellular inclusions known as Lewy bodies. Emerging evidence links αSyn accumulation to impaired lysosomal acidification and defective autophagy-lysosomal degradation, which are central to disease progression. To address this lysosomal dysfunction, we engineered a novel type of lysosome-targeted acidic nanoparticles (AcNPs) based on a biodegradable copolymer, poly(ethylene tetrafluorosuccinate-co-succinate) (PEFSU). These nanomaterials were developed to locally acidify impaired lysosomes and restore their degradative capacity. We evaluated their therapeutic potential in two familial PD models: SH-SY5Y neuroblastoma cells overexpressing A30P αSyn and A30P αSyn transgenic Drosophila melanogaster. In vitro, AcNPs effectively restored lysosomal pH, enhanced autophagic clearance of αSyn, improved mitochondrial function, and rescued A30P αSyn-induced cytotoxicity. In vivo, AcNPs treatment reduced αSyn burden, preserved dopaminergic neurons, and improved motor function in flies. This study demonstrates the first application of lysosome-acidifying polymeric nanoparticles in familial PD models and highlights the promise of rationally engineered pH-modulating nanomaterials as therapeutic agents for PD and other neurodegenerative diseases driven by lysosomal dysfunction and protein aggregation.

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Competing interests

J.Z. is a co‐inventor of a patent registered with the United States Patent and Trademark Office (Patent number: US10925975B2). This patent focuses on the utilization of acidic nanoparticles as a therapeutic approach for diseases characterized by compromised lysosomal acidity. The remaining authors declare no additional competing interests.

PubMed

Nanoparticles That Acidify Cell Recycling Compartments Reduce Neuron Death Caused by A30P α-Synuclein in Cell and Fruit Fly Models of Parkinson's Disease

Abstract

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Competing interests

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