Complement C1q-Targeted Microglial Membrane Camouflaged Nanolipid Carriers for Synaptic Protection in Alzheimer’s Disease: A Bioinspired Alectinib Delivery Strategy

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.