Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30332-0002, United States.
Department of Pediatrics, Emory School of Medicine, Atlanta, Georgia 30322, United States.
Biomacromolecules. 2020 Jul 13;21(7):2635-2644. doi: 10.1021/acs.biomac.0c00264. Epub 2020 May 29.
Cytokine signaling is challenging to study and therapeutically exploit as the effects of these proteins are often pleiotropic. A subset of cytokines can, however, achieve signal specificity via association with latency-inducing proteins, which cage the cytokine until disrupted by discreet biological stimuli. Inspired by this precision, here, we describe a strategy for synthetic induction of cytokine latency via modification with photolabile polymers that mimic latency while attached then restore protein activity in response to light, thus controlling the magnitude, duration, and location of cytokine signals. We characterize the high dynamic range of cytokine activity modulation and find that polymer-induced latency, alone, can prolong in vivo circulation and bias receptor subunit binding. We further show that protein derepression can be achieved with a near single-cell resolution and demonstrate the feasibility of transcutaneous photoactivation. Future extensions of this approach could enable multicolor, optical reprogramming of cytokine signaling networks and more precise immunotherapies.
细胞因子信号转导很难研究和治疗，因为这些蛋白质的作用往往是多效性的。然而，一些细胞因子可以通过与诱导潜伏期的蛋白质结合来实现信号特异性，这些蛋白质将细胞因子困住，直到被特定的生物刺激物破坏。受此启发，在这里，我们描述了一种通过用光不稳定聚合物修饰来合成诱导细胞因子潜伏期的策略，这种聚合物在附着时模拟潜伏期，然后在光的响应下恢复蛋白质活性，从而控制细胞因子信号的幅度、持续时间和位置。我们描述了细胞因子活性调节的高动态范围，并发现聚合物诱导的潜伏期本身可以延长体内循环并偏向受体亚基结合。我们进一步表明，蛋白去阻遏可以达到接近单细胞分辨率，并证明了经皮光激活的可行性。该方法的进一步扩展可以实现细胞因子信号网络的多色、光学重编程和更精确的免疫疗法。
