Targeting the interplay between pathological hallmarks via a lipid hybrid nanozyme to activate synergy therapy of Alzheimer’s disease

Alzheimer’s disease (AD) is locked in a self-amplifying loop of amyloid-β (Aβ) deposition, neurofibrillary tangles (NFTs) and chronic neuroinflammation that has defied every single-target drug to date. We therefore engineered Asi-PtL, a rabies-virus-glycoprotein (RVG)-decorated lipid-hybrid nanozyme that co-loads the pleiotropic natural small-molecule asiaticoside (Asi) and a platinum (Pt) nanozyme, converting two independent bioactivities into one synchronized therapeutic pulse. After intravenous injection, RVG-decorated lipid directs Asi-PtL across the blood–brain barrier and enriches it 3.68-fold higher in brain parenchyma than its non-targeted counterpart. The resulting pharmacological-catalytic synergy erodes the AD triad in vivo: Aβ plaque load plummets by 83.60% and NFT density by 69.11%, while neuroinflammation is extinguished more effectively than with either Asi or nanozyme alone. Proteomic analyses attribute the anti–inflammatory efficacy to the restoration of microglial mitochondrial fitness, encompassing mitigation of oxidative damage, reprogramming of glycolysis and oxidative phosphorylation, and re–establishment of bioenergetic homeostasis. Asi–PtL represents a multi–target nanomedicine that consolidates diverse therapeutic requirements within a single administrable agent, offering a promising strategy for Alzheimer’s disease intervention.