Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Sci Adv. 2021 Jan 1;7(1). doi: 10.1126/sciadv.abd6889. Print 2021 Jan.
Small interfering RNA (siRNA)-based therapeutics can mitigate the long-term sequelae of traumatic brain injury (TBI) but suffer from poor permeability across the blood-brain barrier (BBB). One approach to overcoming this challenge involves treatment administration while BBB is transiently breached after injury. However, it offers a limited window for therapeutic intervention and is applicable to only a subset of injuries with substantially breached BBB. We report a nanoparticle platform for BBB pathophysiology-independent delivery of siRNA in TBI. We achieved this by combined modulation of surface chemistry and coating density on nanoparticles, which maximized their active transport across BBB. Engineered nanoparticles injected within or outside the window of breached BBB in TBI mice showed threefold higher brain accumulation compared to nonengineered PEGylated nanoparticles and 50% gene silencing. Together, our data suggest that this nanoparticle platform is a promising next-generation drug delivery approach for the treatment of TBI.
基于小干扰 RNA（siRNA）的疗法可以减轻创伤性脑损伤（TBI）的长期后遗症，但在血脑屏障（BBB）中渗透性差。克服这一挑战的一种方法是在损伤后 BBB 短暂破裂时进行治疗。然而，这种方法提供的治疗干预窗口有限，并且仅适用于 BBB 严重破裂的一部分损伤。我们报告了一种用于 TBI 中 siRNA 的与 BBB 病理无关的纳米颗粒给药平台。我们通过对纳米颗粒表面化学和涂层密度进行联合调节来实现这一目标，这最大限度地提高了它们穿过 BBB 的主动转运。与非工程化的聚乙二醇化纳米颗粒相比，在 TBI 小鼠的 BBB 破裂窗口内或外注射的工程化纳米颗粒在大脑中的积累增加了三倍，基因沉默率达到 50%。总之，我们的数据表明，这种纳米颗粒平台是治疗 TBI 的一种很有前途的下一代药物输送方法。
