Engineering ApoE3-Targeted NIR-Responsive Liposomes for Multimodal Inhibition of Amyloid-β Aggregation and Acetylcholinesterase Activity.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cognitive decline, largely driven by amyloid-β (Aβ) aggregation and dysregulated acetylcholinesterase (AChE) activity. While current pharmacological interventions utilize AChE inhibitors and Aβ antagonists, their efficacy is frequently hampered by monotherapeutic limitations, poor blood-brain barrier (BBB) permeability, and a lack of controlled release mechanisms. Herein, we report the engineering of the liposomal formulation coloaded with Donepezil (DNP) and the photothermal agent indocyanine green (ICG), followed by conjugation of ApoE3 protein (LIDA) designed for multimodal AD therapy. Surface-conjugated ApoE3 serves a bifunctional role by facilitating BBB penetration and actively inhibiting Aβ oligomerization. Upon 808 nm laser irradiation, ICG-mediated photothermal induction triggers the spatiotemporal release of DNP, significantly enhancing AChE inhibition. Furthermore, LIDA treatment effectively mitigates Aβ-induced cytotoxicity and mitochondrial dysfunction in SH-SY5Y cells. By integrating targeted delivery with NIR responsiveness, this study presents a novel, multivalent strategy to combat the complex pathological landscape of AD.