Ultrasound‐enhanced delivery of donepezil and poly (β‐amino ester) nanoparticles via astrocyte‐derived exosomes in promoting amyloid‐β clearance and supporting neuronal regeneration

Abstract This study examined the combined therapeutic advantages of ultrasound‐enhanced delivery of DPZ with astrocyte‐derived exosomes (ADEs) loaded with poly (β‐amino ester) (PBAE) nanoparticles (NPs) in an SH‐SY5Y cell‐based model of Alzheimer's disease (AD). PBAE‐DPZ NPs were synthesized with excellent yield and later encapsulated into ADEs using electroporation to create stable nanocomposites with pH‐ and ultrasound‐responsive drug release kinetics. Exposure of SH‐SY5Y cells to Aβ42 led to significant upregulation of amyloidogenic genes (APP, BACE1) and downregulation of neuroprotective and regenerative genes (NEP, BDNF, GAP43, SOD1). These molecular alterations were associated with reduced cell viability, increased reactive oxygen species (ROS) generation, and disrupted neurite extension. Administration of ADE‐PBAE‐DPZ nanocomposites effectively reversed these pathological changes. The therapeutic effects were further improved with co‐treatment with focused ultrasound (FUS) as reflected by restoration of gene expression patterns, stimulation of Aβ clearance, improvement of cell viability, decrease in oxidative stress, and induction of neurite regeneration. FUS remarkably promoted exosome uptake, thus further increasing intracellular delivery of DPZ and improving overall efficacy. Additionally, the use of ADE‐PBAE‐DPZ and FUS independent of Aβ42 resulted in favorable results, suggesting a potential role for these treatments in preventive use. These outcomes further justified the potential application of ultrasound‐assisted ADE‐mediated delivery of PBAE‐DPZ as a novel and efficient strategy for targeting key pathological features of AD.