ACS applied materials & interfacesJul 13, 2026

A Nanoparticle System Carrying Donepezil for Alzheimer's Disease that Boosts Cell Cleanup and Reduces Brain Inflammation

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 14, 2026

Abstract

RDB demonstrated significant efficacy in APP/PS1 transgenic AD mice, markedly reducing hippocampal expression of GFAP and Iba-1.

A multitarget synergistic approach for Alzheimer's disease therapy is explored using an oxidative stress-responsive nanocomposite.
The system utilizes bovine serum albumin to cross the blood-brain barrier through receptor-mediated endocytosis.
In the presence of elevated hydrogen peroxide levels in the AD brain, the nanocomposite releases donepezil and RuO₂-TPP in response to oxidative stress.
RuO₂-TPP targets mitochondria, interrupts oxidative stress, repairs mitochondrial dysfunction, and activates the process of removing damaged mitochondria.
RDB promotes the transition of microglia from a pro-inflammatory state to an anti-inflammatory state, altering the inflammatory environment in Alzheimer's disease.

Simplified

A paradigm shift from single-target interventions toward multitarget synergistic actions is increasingly recognized as a promising therapeutic approach for Alzheimer's disease (AD). Given this, an oxidative stress-responsive nanocomposite, RuO₂-TPP/Don@BSA (RDB), was developed to enable effective AD therapy via a "cocktail strategy". Utilizing bovine serum albumin (BSA), the system crosses the blood-brain barrier (BBB) through gp60 receptor-mediated endocytosis. Within the AD brain microenvironment, RDB undergoes disulfide bond cleavage in response to elevated H₂O₂ levels, thereby releasing donepezil (Don) and RuO₂-TPP in a stimuli-responsive manner. Meanwhile, RuO₂-TPP escapes from lysosomes, targets mitochondria, and interrupts the oxidative stress cascade, further repairing mitochondrial dysfunction and activating mitophagy. Moreover, RDB promotes the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby reshaping the inflammatory microenvironment of AD. Finally, RDB demonstrated significant efficacy in APP/PS1 transgenic AD mice, markedly reducing hippocampal expression of GFAP and Iba-1, concomitant with a notable improvement in cognitive dysfunction. In summary, these findings establish RDB as a multitarget synergistic therapeutic system that offers a promising strategy for the treatment of AD.

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A Nanoparticle System Carrying Donepezil for Alzheimer's Disease that Boosts Cell Cleanup and Reduces Brain Inflammation

Abstract

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