Inhibition\nof Aβ Aggregation and Tau Phosphorylation\nwith Functionalized Biomimetic Nanoparticles for Synergic Alzheimer’s\nDisease Therapy

The\nmain pathological mechanisms of Alzheimer’s Disease\n(AD) are extracellular senile plaques caused by β-amyloid (Aβ)\ndeposition and intracellular neurofibrillary tangles derived from\nhyperphosphorylated Tau protein (p-Tau). However, it is difficult\nto obtain a good curative effect because of the poor brain bioavailability\nof drugs, which is attributed to the blood-brain barrier (BBB) restriction\nand complicated brain conditions. Herein, HM-DK was proposed for synergistic\ntherapy of AD by using hollow mesoporous manganese dioxide (HM) as\na carrier to deliver an Aβ-inhibiting peptide and a Dp-peptide\ninhibitor of Tau-related fibril formation synergistically. Inspired\nby 4T1 cancer cells promoting BBB penetration during brain metastasis,\na prospective biomimetic nanocarrier (HM-DK@CM) encapsulated by 4T1\ncell membranes was designed. After crossing the BBB, HM-DK@CM inhibited\nAβ aggregation and prevented Tau phosphorylation simultaneously.\nMoreover, by taking advantage of the catalase-like activity of HM,\nHM-DK@CM relieved oxidative stress and altered the microenvironment\nassociated with the development of AD. Compared with the single therapeutic\ndrug, HM-DK@CM restored nerve damage and improved AD mice’s\nlearning and memory abilities by decreasing Aβ oligomer, p-Tau\nprotein, and inflammation through various pathways for synergistic\ntherapy, which has broad prospects for the effective treatment of\nAD.