Hybrid Lipoplex Boosts Neuron‐Microglia Crosstalk for Treatment of Alzheimer's Disease through A <i>β</i> ‐Targeted‐Autophagy and ApoE2 Gene Supplementation

Efficient clearance of amyloid-β (Aβ) 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@CeO₂) to form RMC assembly for pApoE2 delivery (RMC/pApoE2 lipoplex). The OA@CeO₂ boosts macro-autophagy, alleviates oxidative stress and inflammatory microenvironment, and promotes the neurons-microglia crosstalk for Aβ elimination. Concurrently, both guanidine-rich lipids and OA@CeO₂ benefit pApoE2 transfection in neurons, enabling the transport of Aβ into microglia, and facilitating enzymatic hydrolysis and cellular digestion of extracellular Aβ. The lipoplex-boosted neuron-microglia interactions ultimately eliminate both intra- and extra-cellular Aβ aggregates. Consequently, the RMC/pApoE2 lipoplex eliminates ≈86.9% of Aβ 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 Aβ clearance in AD treatment.