Dysfunctional microglia-targeted nanoscavenger synergistically accelerates Aβ clearance and inhibits inflammatory cascade

Amyloid-β (Aβ) clearance holds promise in Alzheimer's disease (AD) treatment, but the clinical application is limited by poor clearance efficacy and microglial inflammatory cascade caused by overloaded Aβ degradation. In this study, a polymeric lipoprotein-curcumin nanoscavenger (CP/ Man Disc-Cur) with dysfunctional microglia-specific targeting capability is designed to synergistically promote Aβ clearance and inhibit microglial inflammatory cascade. For preparation, curcumin is post-encapsulated into mannose-modified Disc ( Man Disc-Cur), followed by assembly with chitosan derivatives (CP) to obtain CP/ Man Disc-Cur. After intranasal administration and triggered by the nasal acidic microenvironment, CP/ Man Disc-Cur is depolymerized into Man Disc-Cur and protonated CP that adheres to reversibly open the tight junctions, promoting Man Disc-Cur penetration into the brain via the olfactory pathway. Thereafter, Man Disc-Cur captures Aβ oligomer with a high binding affinity (K D  = 5.90 × 10 −8  M) and selectively targets dysfunctional microglia where Aβ catabolism is accelerated with inflammation inhibition by curcumin. After nasal treatment of CP/ Man Disc-Cur for 4 weeks, Aβ burden, microglial inflammation, and memory deficits of APPswe/PS1dE9 transgenic AD mice are significantly attenuated without the obvious side effects. Collectively, this study provides a promising strategy for synergistically improving Aβ clearance and inhibiting microglial inflammatory cascade for enhanced AD treatment.