Customized Intranasal Hydrogel Delivering Methylene Blue Ameliorates Cognitive Dysfunction against Alzheimer's Disease

Abstract The accumulation of hyperphosphorylated tau protein aggregates is a key pathogenic event in Alzheimer's disease (AD) and induces mitochondrial dysfunction and reactive oxygen species overproduction. However, the treatment of AD remains challenging owning to the hindrance caused by the blood–brain barrier (BBB) and the complex pathology of AD. Nasal delivery represents an effective means of circumventing the BBB and delivering drugs to the brain. In this study, black phosphorus (BP) is used as a drug carrier, as well as an antioxidant, and loaded with a tau aggregation inhibitor, methylene blue (MB), to obtain BP‐MB. For intranasal (IN) delivery, a thermosensitive hydrogel is fabricated by cross‐linking carboxymethyl chitosan and aldehyde Pluronic F127 (F127‐CHO) micelles. The BP‐MB nanocomposite is incorporated into the hydrogel to obtain BP‐MB@Gel. BP‐MB@Gel could be injected intranasally, providing high nasal mucosal retention and controlled drug release. After IN administration, BP‐MB is continuously released and delivered to the brain, exerting synergistic therapeutic effects by suppressing tau neuropathology, restoring mitochondrial function, and alleviating neuroinflammation, thus inducing cognitive improvements in mouse models of AD. These findings highlight a potential strategy for brain‐targeted drug delivery in the management of the complex pathologies of AD.