Complement C1q-Targeted Microglial Membrane Camouflaged Nanolipid Carriers for Synaptic Protection in Alzheimer's...

Aberrant activation of the complement system drives early synaptic loss and chronic neuroinflammation in Alzheimer's disease (AD). Here, we identified complement component C1q as a key upregulated target in AD and screened Alectinib (ALE), an FDA-approved kinase inhibitor, as a high-affinity C1q binder. To achieve brain-targeted delivery, ALE was encapsulated in nanostructured lipid carriers camouflaged with microglial membranes (ALE@MM-NLCs). This biomimetic design enhanced blood-brain barrier (BBB) penetration and microglial uptake. In APP/PS1 mice, ALE@MM-NLCs improved cognitive performance and reduced C1q expression, β-amyloid (Aβ) burden, and glial activation, while promoting microglial M2-like polarization. Mechanistically, ALE@MM-NLCs suppressed oxidative stress, NLRP3 inflammasome activation, and C1q-mediated synaptosome phagocytosis, thereby preventing proteasome-dependent synaptic degradation. These results highlight ALE@MM-NLCs as a promising immunomodulatory nanotherapy for synaptic preservation and early AD intervention.