Systemic Administration of Neurotransmitter‐Derived Lipidoids‐PROTACs‐DNA Nanocomplex Promotes Tau Clearance and Cognitive Recovery for Alzheimer's Disease Therapy

Abstract Alzheimer's disease (AD) poses a significant burden on the economy and healthcare systems worldwide. Although the pathophysiology of AD remains debatable, its progression is strongly correlated with the accumulation of tau aggregates. Therefore, tau clearance from brain lesions can be a promising strategy for AD therapy. To achieve this, the present study combined proteolysis‐targeting chimera (PROTAC), a novel protein‐degradation technique that mediates degradation of target proteins via the ubiquitin‐proteasome system, and a neurotransmitter‐derived lipidoid (NT‐lipidoid) nanoparticle delivery system with high blood‐brain barrier‐penetration activity, to generate a novel nanomedicine named NPD. Peptide 1, a cationic tau‐targeting PROTAC is loaded onto the positively charged nanoparticles using DNA‐intercalation technology. The resulting nanomedicine displayed good encapsulation efficiency, serum stability, drug release profile, and blood‐brain barrier‐penetration capability. Furthermore, NPD potently induced tau clearance in both cultured neuronal cells and the brains of AD mice. Moreover, intravenous injection of NPD led to a significant improvement in the cognitive function of the AD mice, without any remarkable abnormalities, thereby supporting its clinical development. Collectively, the novel nanomedicine developed in this study may serve as an innovative strategy for AD therapy, since it effectively and specifically induces tau protein clearance in brain lesions, which in turn enhances cognition.