Synthetic receptors that mediate antigen-dependent cell responses are transforming therapeutics, drug discovery and basic research^1,2. However, established technologies such as chimeric antigen receptors³ can only detect immobilized antigens, have limited output scope and lack built-in drug control^3,4,5,6,7. Here we engineer synthetic G-protein-coupled receptors (GPCRs) that are capable of driving a wide range of native or non-native cellular processes in response to a user-defined antigen. We achieve modular antigen gating by engineering and fusing a conditional auto-inhibitory domain onto GPCR scaffolds. Antigen binding to a fused nanobody relieves auto-inhibition and enables receptor activation by drug, thus generating programmable antigen-gated G-protein-coupled engineered receptors (PAGERs). We create PAGERs that are responsive to more than a dozen biologically and therapeutically important soluble and cell-surface antigens in a single step from corresponding nanobody binders. Different PAGER scaffolds allow antigen binding to drive transgene expression, real-time fluorescence or endogenous G-protein activation, enabling control of diverse cellular functions. We demonstrate multiple applications of PAGER, including induction of T cell migration along a soluble antigen gradient, control of macrophage differentiation, secretion of therapeutic antibodies and inhibition of neuronal activity in mouse brain slices. Owing to its modular design and generalizability, we expect PAGERs to have broad utility in discovery and translational science.

介导抗原依赖性细胞反应的合成受体正在改变治疗学、药物发现和基础研究^1,2。然而，嵌合抗原受体³ 等成熟技术只能检测固定化抗原，输出范围有限，并且缺乏内置的药物控制^3,4,5,6,7。在这里，我们设计了合成的 G 蛋白偶联受体 （GPCR），它们能够响应用户定义的抗原来驱动广泛的天然或非天然细胞过程。我们通过将条件性自身抑制结构域工程化并融合到 GPCR 支架上来实现模块化抗原门控。抗原与融合纳米抗体的结合可减轻自身抑制，并使药物激活受体，从而产生可编程抗原门控 G 蛋白偶联工程受体 （PAGER）。我们从相应的纳米抗体结合剂中一步创建对十几种具有生物学和治疗意义的可溶性和细胞表面抗原有反应的 PAGER。不同的 PAGER 支架允许抗原结合驱动转基因表达、实时荧光或内源性 G 蛋白激活，从而能够控制不同的细胞功能。我们展示了 PAGER 的多种应用，包括沿可溶性抗原梯度诱导 T 细胞迁移、控制巨噬细胞分化、治疗性抗体的分泌和抑制小鼠脑切片中的神经元活动。由于其模块化设计和通用性，我们预计 PAGER 将在发现和转化科学中具有广泛的用途。