The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune modulation and a delivery system capable of crossing the blood–brain barrier. The recent identification and characterization of a small population of regulatory T (T_reg) cells resident in the brain presents one such potential therapeutic target. Here, we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident T_reg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected in traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.

免疫调节生物制剂预防和逆转病理的能力已经改变了最近的临床实践。然而，在神经炎症领域的充分利用需要确定局部免疫调节的有效靶点和能够穿过血脑屏障的递送系统。最近对大脑中一小群调节性 T (T _{reg ) 细胞的鉴定和表征提出了一个这样的潜在治疗靶点。}在这里，我们确定大脑白细胞介素 2 (IL-2) 水平是大脑驻留 T _reg细胞的限制因素。我们开发了一种星形胶质细胞的基因传递方法，通过小分子开关来实现时间控制，并增强反应性星形胶质细胞的产量，以在空间上直接传递到炎症部位。大脑特异性 IL-2 递送的小鼠在脑外伤、中风和多发性硬化症模型中受到保护，且不影响外周免疫系统。这些结果验证了大脑特异性 IL-2 基因递送能够有效预防神经炎症，并为向神经炎症患者递送多种生物制剂提供了一个多功能平台。