Abstract

Intervention of the over-activated microglia-aggravated neuroinflammation represents a promising therapeutic strategy for Alzheimer's disease (AD). Upregulation of triggering receptor expressed on myeloid cells-2 (TREM2) attenuates the neuroinflammatory processes and normalizes the dysfunctional microglia . However, Trem2 -gene therapy for AD by the effective non-invasive delivery systems is unexploited. Herein, we report the microglia-targeted gene delivery systems ( [email protected] /pTREM2) composed of a core of fluorinated polyethylenimine condensing the TREM2-encoding plasmid (PF/pTREM2) and a shell of human serum albumin conjugated with both cis -aconitic anhydride and neural cell adhesion molecule-mimetic peptide P2 (PHSA). Thanks to the shedding effect of the albumin coated, [email protected] /pTREM2 exhibit prolonged blood circulation and low cytotoxicity. [email protected] /pTREM2 achieve brain accumulation as high as 2.17% injected dose per gram of brain and the microglial-targeting effect (targeting specificity of 41.9%) via the systemic administration. The nanocomplexes can be detached PHSA-shell in the acidic endo-lysosomes via the cleavage of cis -aconitic amide bond, resulting in PF/pTREM2 exposure for efficient endo-lysosomal escape and gene transfection. [email protected] /pTREM2 upregulate the TREM2 level and regulate microglial polarization toward M2-phenotype for remodeling the inflammatory microenvironment and enhanced Aβ clearance, leading to an improvement of cognitive performance in APP/PS1 mice. This work provides a promising gene delivery platform to reverse dysfunctional microglia for AD therapy.