Nasal delivery of polymeric nanoDisc mobilizes a synergy of central and peripheral amyloid- clearance to treat Alzheimer's disease

The disequilibrium of amyloid beta-peptide (A beta) between the central and peripheral pools has been claimed as an initiating event in Alzheimer's disease (AD). In this study, we employ discoidal high- density lipoproteins (HDL-Disc) mimicking A beta antibody for directional flux of A beta from central to peripheral catabolism, with desirable safety and translation potential. Structurally, HDL-Disc assembly (polyDisc) is prepared with aid of chitosan derivative polymerization. After intranasal administration and response to slightly acidic nasal microenvironment, polyDisc depolymerizes into carrier -free HDL-Disc with chitosan derivatives that adhere to the mucosal layer to reversibly open tight junctions, helping HDL-Disc penetrate the olfactory pathway into brain. Thereafter, HDL-Disc captures A beta into microglia for central clearance or ferries A beta out of the brain for liver- mediated compensatory catabolism. For synergy therapy, intranasal administration of polyDisc can effectively reduce intracerebral A beta burden by 97.3% and vascular A beta burden by 73.5%, ameliorate neurologic damage, and rescue memory deficits in APPswe/PS1dE9 transgenic AD mice with improved safety, especially vascular safety. Collectively, this design provides a proof of concept for developing A beta antibody mimics to mobilize a synergy of central and peripheral A beta clearance for AD treatment.