The inflammatory dysfunction of microglia from excess amyloid-β peptide (Aβ) disposal is an overlooked but pathogenic event in Alzheimer's disease (AD). Here, we exploit a native high-density lipoprotein (HDL)-inspired nanoscavenger (pHDL/Cur-siBACE1) that combines the trinity of phosphatidic acid-functionalized HDL (pHDL), curcumin (Cur), and β-site APP cleavage enzyme 1 targeted siRNA (siBACE1) to modulate microglial dysfunction. By mimicking the natural lipoprotein transport route, pHDL can penetrate the blood−brain barrier and sequentially target Aβ plaque, where Aβ catabolism is accelerated without microglial dysfunction. The benefit results are from a three-pronged modulation strategy, including promoted Aβ clearance with an antibody-like Aβ binding affinity, normalized microglial dysfunction by blocking the NF-κB pathway, and reduced Aβ production by gene silence (44%). After treatment, the memory deficit and neuroinflammation of APPswe/PSEN 1dE9 mice are reversed. Collectively, this study highlights the doubleedged sword role of microglia and provides a promising tactic for modulating microglial dysfunction in AD treatment.
Amyloid‐β (Aβ) toxicity is considered to be companioned by Tau phosphorylation in Alzheimer's disease (AD). The clinical AD therapy is usually subjected to low blood‐brain barrier (BBB) penetration and complex interaction mechanisms between Aβ and phosphorylated Tau. A “Drug‐Carrier” synergy therapy is herein designed to simultaneously target Aβ and Tau‐associated pathways for AD treatment. To imitate natural nanoparticle configuration, the endogenous apolipoprotein A‐I and its mimicking peptide 4F fused angiopep‐2 (Ang) are sequentially grafted onto lipid nanocomposite (APLN), providing liberty of BBB crossing and microglia targeted Aβ clearance. For synergy treatment, methylene blue (MB) is further assembled into APLN (APLN/MB) for Tau aggregation inhibition. After intravenous administration, the optimized density (5 wt%) of Ang ligands dramatically enhances APLN/MB intracerebral shuttling and accumulation, which is 2.15‐fold higher than that Ang absent‐modification. The site‐specific release of MB collaborates APLN to promote Aβ capture for microglia endocytosis clearance and reduce p‐Tau level by 25.31% in AD pathogenesis. In AD‐Aβ–Tau bearing mouse models, APLN/MB can relieve AD symptoms, rescue neuron viability and cognitive functions. Collectively, it is confirmed that “Drug‐Carrier” synergy therapy of APLN/MB is a promising approach in the development of AD treatments.
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