Intranasal Delivery of Pure Nanodrug Loaded Liposomes for Alzheimer's Disease Treatment by Efficiently Regulating Microglial Polarization

Abstract The activated M1‐like microglia induced neuroinflammation is the critical pathogenic event in Alzheimer's disease (AD). Microglial polarization from pro‐inflammatory M1 toward anti‐inflammatory M2 phenotype is a promising strategy. To efficiently accomplish this, amyloid‐β (Aβ) aggregates as the culprit of M1 microglia activation should be uprooted. Interestingly, this study finds out that the self‐reassembly of curcumin molecules into carrier‐free curcumin nanoparticles (CNPs) exhibits multivalent binding with Aβ to achieve higher inhibitory effect on Aβ aggregation, compared to free curcumin with monovalent effect. Based on this, the CNPs loaded cardiolipin liposomes are developed for efficient microglial polarization. After intranasal administration, the liposomes decompose to release CNPs and cardiolipin in response to AD oxidative microenvironment. The CNPs inhibit Aβ aggregation and promote Aβ phagocytosis/clearance in microglia, removing roadblock to microglial polarization. Subsequently, CNPs are endocytosed by microglia and inhibit TLR4/NF‐κB pathway for microglia polarization (M1→M2). Meanwhile, cardiolipin is identified as signaling molecule to normalize microglial dysfunction to prevent pro‐inflammatory factors release. In AD transgenic mice, neuroinflammation, Aβ burden, and memory deficits are relieved after treatment. Through combined attack by extracellularly eradicating roadblock of Aβ aggregation and intracellularly inhibiting inflammation‐related pathways, this nanotechnology assisted delivery system polarizes microglia efficiently, providing a reliable strategy in AD treatment.