Hybrid Lipoplex Boosts Neuron‐Microglia Crosstalk for Treatment of Alzheimer's Disease through Aβ‐Targeted‐Autophagy and ApoE2 Gene Supplementation

Abstract Efficient clearance of amyloid‐ β (A β ) is vital but challenging in Alzheimer's disease (AD) treatment due to its complicated regulation mechanisms during generation and metabolism. It necessitates a multidimensional synergistic strategy based on ingenious delivery system design. Herein, guanidine‐rich lipids (metformin‐inspired MLS and arginine‐contained RLS) are devised to trigger selective chaperone‐mediated autophagy for amyloid precursor protein degradation in neurons. They are further co‐assembled with oleic acid‐modified cerium dioxide (OA@CeO 2 ) to form RMC assembly for pApoE2 delivery (RMC/pApoE2 lipoplex). The OA@CeO 2 boosts macro‐autophagy, alleviates oxidative stress and inflammatory microenvironment, and promotes the neurons‐microglia crosstalk for A β elimination. Concurrently, both guanidine‐rich lipids and OA@CeO 2 benefit pApoE2 transfection in neurons, enabling the transport of A β into microglia, and facilitating enzymatic hydrolysis and cellular digestion of extracellular A β . The lipoplex‐boosted neuron–microglia interactions ultimately eliminate both intra‐ and extra‐cellular A β aggregates. Consequently, the RMC/pApoE2 lipoplex eliminates ≈86.9% of A β plaques in the hippocampus of APP/PS1 mice and restored the synaptic function and neuronal connectivity. Moreover, it recovers the spatial memory of APP/PS1 mice to nearly the level of WT control. The presented hybrid lipoplex showcases an advanced gene delivery system, and offers a promising strategy for A β clearance in AD treatment.