Endo/Lysosome‐Escapable Delivery Depot for Improving BBB Transcytosis and Neuron Targeted Therapy of Alzheimer's Disease

Abstract The effective treatment of Alzheimer's disease (AD) is hindered due to the hard blood–brain barrier (BBB) penetration and non‐selective distribution of drugs in the brain. Moreover, the complicated pathological mechanism of AD involves various pathway dysfunctions that limit the effectiveness of a single therapeutic drug. Herein, a dendrigraft poly‐ l ‐lysines (DGL)‐based siRNA and D peptide (Dp) loaded nanoparticle is designed that could target and penetrate through the BBB, enter the brain parenchyma, and further accumulate at the AD lesion. In this system, T7 peptide, which specifically targets transferrin receptors on the BBB, is linked to DGL via acid‐cleavable long polyethylene glycol (PEG) to achieve high internalization, quick escape from endo/lysosome, and effective transcytosis. Then, the Tet1, which specifically targets diseased neurons, is modified onto DGL by short PEG. After being exposed, Tet1 could drive the nanoparticles to the AD lesion and release the drugs. As a result, the production of β amyloid plaques (Aβ) is inhibited. Neurotoxicity induced by Aβ plaques and tau proten phosphorylation (p‐tau) tangle is also alleviated, and the cognition of AD mice is significantly improved. Overall, this system programmatically targets BBB and neurons, thus, significantly enhances the intracephalic drug accumulation and AD treatment efficacy.