A Single‐Molecule Pleuripotent Scaffold for Combinational Therapy of Alzheimer's Disease via Intranasal Administration

Herein, guanidinium‐modified calix[5]arene (GC5AY) is developed featuring small size, positive charge, and desirable amphiphilicity, that can efficiently traverse the nasal mucosal barrier for brain drug delivery. Additionally, possessing inherent therapeutic functions, GC5AY can thus serve as a single‐molecule pleuripotent scaffold for multi‐target combinational therapy of Alzheimer's disease via intranasal administration. Abstract The intricate pathological mechanisms of Alzheimer's disease (AD), along with the restrictive nature of the blood‐brain barrier (BBB) that further impedes the drug brain entry, underscore the pressing need for innovative combinational therapy to achieve effective treatment outcomes. Intranasal administration, capable of bypassing BBB by direct transport through olfactory and trigeminal nerves, provides a promising approach for treating neurological disorders. Herein, the guanidinium‐modified calix[5]arene (GC5AY) is developed as a single‐molecule pleuripotent scaffold, demonstrating small size, positive charge and desirable amphiphilicity, which facilitate its efficient traverse of nasal mucosal barrier. The multifunctionality of GC5AY, including inhibiting amyloid fibrosis, scavenging reactive oxygen species and drug delivery, enables it to serve as a sophisticated platform for constructing multi‐target AD therapeutic agents. In light of this, by loading neuroprotective agent Trilobatin (TLB) into the cavity of GC5AY, intranasal administration of the TLB@GC5AY formulation is verified to effectively attenuate the cognitive impairment of AD mice, demonstrating multifaceted pathological improvements, while also possessing good biocompatibility. In response to the growing appeal for combinational therapy of AD, the approach proposed in this study has provided a readily generalizable strategy to fulfill this pursuit. Herein, guanidinium-modified calix[5]arene (GC5AY) is developed featuring small size, positive charge, and desirable amphiphilicity, that can efficiently traverse the nasal mucosal barrier for brain drug delivery. Additionally, possessing inherent therapeutic functions, GC5AY can thus serve as a single-molecule pleuripotent scaffold for multi-target combinational therapy of Alzheimer's disease via intranasal administration. Abstract The intricate pathological mechanisms of Alzheimer's disease (AD), along with the restrictive nature of the blood-brain barrier (BBB) that further impedes the drug brain entry, underscore the pressing need for innovative combinational therapy to achieve effective treatment outcomes. Intranasal administration, capable of bypassing BBB by direct transport through olfactory and trigeminal nerves, provides a promising approach for treating neurological disorders. Herein, the guanidinium-modified calix[5]arene (GC5AY) is developed as a single-molecule pleuripotent scaffold, demonstrating small size, positive charge and desirable amphiphilicity, which facilitate its efficient traverse of nasal mucosal barrier. The multifunctionality of GC5AY, including inhibiting amyloid fibrosis, scavenging reactive oxygen species and drug delivery, enables it to serve as a sophisticated platform for constructing multi-target AD therapeutic agents. In light of this, by loading neuroprotective agent Trilobatin (TLB) into the cavity of GC5AY, intranasal administration of the TLB@GC5AY formulation is verified to effectively attenuate the cognitive impairment of AD mice, demonstrating multifaceted pathological improvements, while also possessing good biocompatibility. In response to the growing appeal for combinational therapy of AD, the approach proposed in this study has provided a readily generalizable strategy to fulfill this pursuit. Advanced Science, Volume 12, Issue 43, November 20, 2025.