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

The accumulation of amyloid-β (Aβ) 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 Aβ 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 Aβ 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 Aβ monomers and oligomers, and disintegration of pre-formed Aβ 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 Aβ by microglia and neurons through lysosomal transport and elimination approaches. Four-week administration of RLA-rHDL@ANG effectively reduced Aβ 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.