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.
摘要：
过度磷酸化tau蛋白聚集体的积累是阿尔茨海默病（AD）的关键致病事件，并诱导线粒体功能障碍和活性氧（ROS）过度产生。然而,由于血脑屏障（BBB）和AD的复杂病理造成的障碍，AD的治疗仍然具有挑战性。经鼻递送代表了规避BBB和将药物递送至脑的有效手段。在这项研究中,黑磷（BP）被用作药物载体和抗氧化剂，并负载有tau聚集抑制剂，亚甲蓝(MB),获得BP-MB。对于鼻内递送，我们通过交联羧甲基壳聚糖（CMCS）和醛PluronicF127（F127-CHO）胶束制备了热敏水凝胶。将BP-MB纳米复合材料掺入水凝胶中以获得BP-MB@凝胶。BP-MB@Gel可以鼻内注射，提供高的鼻粘膜保留和控制药物释放。鼻内给药后,BP-MB不断释放并传递到大脑，通过抑制tau神经病理学发挥协同治疗作用，恢复线粒体功能,缓解神经炎症，从而诱导AD小鼠模型的认知改善。这些发现突出了脑靶向药物递送在AD复杂病理管理中的潜在策略。本文受版权保护。保留所有权利。
