Versatile lipoprotein-inspired nanocomposites rescue Alzheimer's cognitive dysfunction by promoting Aß degradation and lessening oxidative stress.

The accumulation of amyloid-ß (Aß) into senile plaques and the resulting continuous oxidative stress are major pathogenic mechanisms in Alzheimer's disease (AD). In this study, we designed a lipoprotein-inspired nanoparticle to facilitate Aß clearance and alleviate oxidative stress for the treatment of AD. Lipoprotein-like nanocomposites (RLA-rHDL@ANG) were fabricated by assembling reconstituted high density lipoprotein (rHDL) with an apoE-derived peptide (RLA) with Aß binding and clearance capabilities, and were subsequently camouflaged using reactive oxygen species (ROS)-sensitive DSPE-TK-mPEG2000 and DSPE-TK-PEG3400-ANG with brain penetration as well as ROS scavenging ability. Immunoelectron microscopy, fluorescence colocalization, and enzyme linked immunosorbent assay, together with a thioflavin-T (ThT) fluorescence quantitative test, showed that RLA-rHDL@ANG possessed the ability of high binding affinity to both Aß monomers and oligomers, and disintegration of pre-formed Aß aggregates. ROS level monitoring and transmission electron microscopy (TEM) showed that RLA-rHDL@ANG possessed ROS sensitivity and consumption properties. Transcellular assay and in vivo imaging showed that RLA-rHDL@ANG effectively facilitated blood-brain barrier (BBB) penetration and intracerebral accumulation. It promoted the efficient degradation of Aß by microglia and neurons through lysosomal transport and elimination approaches. Four-week administration of RLA-rHDL@ANG effectively reduced Aß deposition, decreased the ROS level and improved cognitive functions in AD mice. These findings indicate that multifunctional RLA-rHDL@ANG may serve as a promising and feasible candidate for managing the progression of AD.