Nanoparticles have been widely adopted in nasal drug delivery for the treatment of brain diseases. However, the feasibility of nose-to-brain transportation of intact nanoparticles and the possible corresponding pathways remain poorly understood. In this study, nose-to-brain delivery of mPEG-PDLLA micelles (PMs) and TAT functionalized ones (TAT-PMs) were explored by labeling with aggregation-caused quenching (ACQ) probes, which provide on-to-off fluorescent switching from loaded to released states for identification of the intact nanocarriers. Coumarin-6 was simultaneously loaded in the micelles to mimic cargos. Evidence of nose-to-brain translocation was collected through IVIS live imaging and ex vivo histological imaging. TAT modification reduced the retention of intact micelles in the nasal cavity due to the enhanced absorption and the subsequent distribution to other organs. Trigeminal nerve is the main transportation pathway for nose-to-brain delivery of the intact micelles. TAT modification improves the cellular uptake of the intact micelles and is crucial for micelles to permeate into the olfactory bulb. Nevertheless, cargos are mainly released from the micelles and diffuse into the brain. In conclusion, TAT modification facilitates nose-to-brain delivery of micelles, whereas cargos can be released and permeated into the brain in greater amounts.

纳米颗粒已被广泛用于鼻内药物治疗脑疾病。然而，完整纳米颗粒从鼻到脑运输的可行性以及可能的相应途径仍知之甚少。在这项研究中，通过用聚集引起的猝灭（ACQ）探针进行标记，探索了mPEG-PDLLA胶束（PM）和TAT功能化胶束（TAT-PM）的从鼻到脑的递送，该探针可提供开-关荧光切换从加载状态到释放状态，以鉴定完整的纳米载体。同时将香豆素6装入胶束中以模拟货物。通过IVIS实时成像和离体收集了鼻子到大脑易位的证据组织学成像。由于增强了吸收并随后分布到其他器官，TAT修饰减少了完整胶束在鼻腔中的保留。三叉神经是完整胶束从鼻到脑的主要运输途径。TAT修饰可改善完整胶束的细胞吸收能力，对于胶束渗透到嗅球中至关重要。然而，货物主要是从胶束中释放出来并扩散到大脑中。总之，TAT修饰促进了胶束从鼻到脑的传递，而货物则可以释放并渗透到大脑中。