Co‐Assembled Nanoparticles toward Multi‐Target Combinational Therapy of Alzheimer's Disease by Making Full Use of Molecular Recognition and Self‐Assembly

Abstract The complex pathologies in Alzheimer's disease (AD) severely limit the effectiveness of single‐target pharmic interventions, thus necessitating multi‐pronged therapeutic strategies. While flexibility is essentially demanded in constructing such multi‐target systems, for achieving optimal synergies and also accommodating the inherent heterogeneity within AD. Utilizing the dynamic reversibility of supramolecular strategy for conferring sufficient tunability in component substitution and proportion adjustment, amphiphilic calixarenes are poised to be a privileged molecular tool for facilely achieving function integration. Herein, taking β‐amyloid (Aβ) fibrillation and oxidative stress as model combination pattern, a supramolecular multifunctional integration is proposed by co‐assembling guanidinium‐modified calixarene with ascorbyl palmitate and loading dipotassium phytate within calixarene cavity. Serial pivotal events can be simultaneously addressed by this versatile system, including 1) inhibition of Aβ production and aggregation, 2) disintegration of Aβ fibrils, 3) acceleration of Aβ metabolic clearance, and 4) regulation of oxidative stress, which is verified to significantly ameliorate the cognitive impairment of 5×FAD mice, with reduced Aβ plaque content, neuroinflammation, and neuronal apoptosis. Confronted with the extremely intricate clinical realities of AD, the strategy presented here exhibits ample adaptability for necessary alterations on combinations, thereby may immensely expedite the advancement of AD combinational therapy through providing an exceptionally convenient platform.