The blood–brain barrier (BBB) poses a substantial obstacle to the successful delivery of therapeutics to the central nervous system (CNS). The transnasal route has been extensively explored, but success rates have been modest due to challenges related to the precise anatomical placement of drugs, the small volumes that the olfactory cleft can accommodate and short drug residence times due to mucociliary clearance. Here, to address these issues, we have developed a surgical technique known as the minimally invasive nasal depot (MIND), which allows the accurate placement of depot drugs into the submucosal space of the olfactory epithelium of rats. This technique exploits the unique anatomy of the olfactory apparatus to enable transnasal delivery of drugs into the CNS, bypassing the BBB. In our rat model, a bony window is created in the animal snout to expose the submucosal space. Using the MIND technique, we have successfully delivered oligonucleotides to the CNS in Sprague-Dawley and Long-Evans rats, leading to an upregulation of brain-derived neurotrophic factor in the substantia nigra and hippocampus. In this Protocol, we describe the procedural steps for MIND. This procedure takes about 45 min and can be performed by researchers with basic surgical skills. We additionally describe modifications to perform MIND in mice, which are anatomically smaller. The MIND procedure represents a unique platform that can be used to overcome the limitations posed by the BBB. This technique can potentially expand the therapeutic toolkit in the treatment of neurological diseases.

血脑屏障 （BBB） 对成功向中枢神经系统 （CNS） 提供治疗构成了重大障碍。经鼻途径已被广泛探索，但由于与药物的精确解剖放置、嗅裂可以容纳的小体积以及由于粘膜纤毛清除而导致的药物停留时间短相关的挑战，成功率一直不高。在这里，为了解决这些问题，我们开发了一种称为微创鼻库 （MIND） 的手术技术，该技术允许将长效药物准确放置在大鼠嗅觉上皮的粘膜下空间。该技术利用嗅觉器官的独特解剖结构，绕过 BBB 将药物经鼻输送到 CNS。在我们的大鼠模型中，在动物鼻子中创建了一个骨窗以暴露粘膜下间隙。使用 MIND 技术，我们成功地将寡核苷酸递送到 Sprague-Dawley 和 Long-Evans 大鼠的 CNS，导致黑质和海马体中脑源性神经营养因子的上调。在本协议中，我们描述了 MIND 的程序步骤。此过程大约需要 45 分钟，可以由具有基本手术技能的研究人员进行。我们还描述了在小鼠中执行 MIND 的修饰，小鼠在解剖学上更小。MIND 程序代表了一个独特的平台，可用于克服 BBB 带来的限制。这项技术有可能扩展治疗神经系统疾病的治疗工具包。