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Abstract：
Currently, neurointervention, surgery, medication, and central nervous system (CNS) stimulation are the main treatments used in CNS diseases. These approaches are used to overcome the blood brain barrier (BBB), but they have limitations that necessitate the development of targeted delivery methods. Thus, recent research has focused on spatiotemporally direct and indirect targeted delivery methods because they decrease the effect on nontarget cells, thus minimizing side effects and increasing the patient\'s quality of life. Methods that enable therapeutics to be directly passed through the BBB to facilitate delivery to target cells include the use of nanomedicine (nanoparticles and extracellular vesicles), and magnetic field-mediated delivery. Nanoparticles are divided into organic, inorganic types depending on their outer shell composition. Extracellular vesicles consist of apoptotic bodies, microvesicles, and exosomes. Magnetic field-mediated delivery methods include magnetic field-mediated passive/actively-assisted navigation, magnetotactic bacteria, magnetic resonance navigation, and magnetic nanobots-in developmental chronological order of when they were developed. Indirect methods increase the BBB permeability, allowing therapeutics to reach the CNS, and include chemical delivery and mechanical delivery (focused ultrasound and LASER therapy). Chemical methods (chemical permeation enhancers) include mannitol, a prevalent BBB permeabilizer, and other chemicals-bradykinin and 1-O-pentylglycerol-to resolve the limitations of mannitol. Focused ultrasound is in either high intensity or low intensity. LASER therapies includes three types: laser interstitial therapy, photodynamic therapy, and photobiomodulation therapy. The combination of direct and indirect methods is not as common as their individual use but represents an area for further research in the field. This review aims to analyze the advantages and disadvantages of these methods, describe the combined use of direct and indirect deliveries, and provide the future prospects of each targeted delivery method. We conclude that the most promising method is the nose-to-CNS delivery of hybrid nanomedicine, multiple combination of organic, inorganic nanoparticles and exosomes, via magnetic resonance navigation following preconditioning treatment with photobiomodulation therapy or focused ultrasound in low intensity as a strategy for differentiating this review from others on targeted CNS delivery; however, additional studies are needed to demonstrate the application of this approach in more complex in vivo pathways.
摘要：
目前,神经干预,手术,药物,中枢神经系统（CNS）刺激是CNS疾病的主要治疗方法。这些方法用于克服血脑屏障（BBB），但它们有局限性，需要开发有针对性的交付方法。因此，最近的研究集中在时空直接和间接靶向递送方法，因为它们降低了对非靶细胞的影响，从而减少副作用，提高患者的生活质量。使治疗剂能够直接通过BBB以促进递送至靶细胞的方法包括使用纳米药物（纳米颗粒和细胞外囊泡）。和磁场介导的递送。纳米颗粒分为有机，无机类型取决于它们的外壳组成。细胞外囊泡由凋亡小体组成，微泡,和外泌体。磁场介导的递送方法包括磁场介导的被动/主动辅助导航，趋磁细菌，磁共振导航，和磁性纳米机器人-按照它们被开发时的发展时间顺序。间接方法增加BBB渗透性，允许治疗剂到达中枢神经系统，包括化学输送和机械输送（聚焦超声和激光治疗）。化学方法（化学渗透促进剂）包括甘露醇，一种普遍的BBB渗透剂，和其他化学物质-缓激肽和1-O-戊基甘油-解决甘露醇的局限性。聚焦超声处于高强度或低强度。激光疗法包括三种类型：激光间质疗法，光动力疗法,和光生物调节疗法。直接和间接方法的组合并不像它们的单独使用那样普遍，而是代表了该领域进一步研究的领域。本文旨在分析这些方法的优缺点。描述直接和间接交付的组合使用，并提供每种有针对性的交付方式的未来前景。我们得出的结论是，最有前途的方法是混合纳米药物的鼻子到中枢神经系统的递送，有机的多重组合，无机纳米颗粒和外来体，通过磁共振导航预处理后用光生物调节疗法或低强度聚焦超声作为区分本综述与其他靶向中枢神经系统递送的策略;然而,需要更多的研究来证明这种方法在更复杂的体内途径中的应用.
