Receptor-Ligand-Mediated Anchoring of Polyphenol Quantum Dots to Membrane Fragments for Precision Delivery in Alzheimer's Disease Therapy

Polyphenol-based carbon dots (PCDs) hold great promise for Alzheimer's disease (AD) treatment owing to their inherent antioxidant activity, ultrasmall size, and favorable blood-brain barrier (BBB) permeability. Nevertheless, rapid immune clearance and poor lesion targeting severely hinder their clinical translation. Conventional cell membrane coating is poorly compatible with ultrasmall PCDs, causing incomplete encapsulation, active site masking, and membrane protein inactivation. Herein, we fabricated a novel biomimetic nanostructure (MQCM) by anchoring mannose-modified quercetin nanodots (MQNDs) onto BV2 cell membrane fragments (CMFs) via specific mannose-CD206 receptor-ligand interactions. This unique binding strategy endowed MQCM with a high anchoring efficiency (84.3%) and improved structural stability. Distinct from conventional nonspecific membrane coating that shields active sites and impairs nanoparticle functionality, this design avoids such drawbacks and completely preserves the intrinsic bioactivity of MQNDs and membrane proteins. The optimized MQCM displays high BBB permeability (42.35%), precise BV2 targeting, and lesion-responsive drug release. BV2-derived CMFs prolong blood circulation and lesion retention of MQNDs, while the released MQNDs exert multiple anti-AD effects by regulating ROS homeostasis, inhibiting Aβ fibrillation, and promoting Aβ autophagy. Collectively, this integrated biomimetic system offers a precise AD therapeutic strategy and advances the clinical translation of PCD-based nanomedicines.