The use of combinatorial siRNAs shows great promise for drug discovery, but the identification of safe and effective siRNA combinations remains challenging. Here, we develop a massively multiplexed technology for systematic screening of siRNA-based cocktail therapeutics. We employ composite micro-carriers that are responsive to near infrared light and magnetic field to achieve photoporation-facilitated siRNA transfection to individual cells. Thus, randomized gene silencing by different siRNA formulations can be performed with high-throughput single-cell-based analyses. For screening anti-cancer siRNA cocktails, we test more than 1300 siRNA combinations for knocking down multiple genes related to tumor growth, discovering effective 3-siRNA formulations with an emphasis on the critical role of inhibiting Cyclin D1 and survivin, along with their complementary targets for synergic efficacy. This approach enables orders of magnitude reduction in time and cost associated with largescale siRNA screening, and resolves key insights to siRNA pharmacology that are not permissive to existing methods.

组合 siRNA 的使用在药物发现方面显示出巨大的前景，但鉴定安全有效的 siRNA 组合仍然具有挑战性。在这里，我们开发了一种大规模多重技术，用于系统筛选基于 siRNA 的鸡尾酒疗法。我们采用对近红外光和磁场有反应的复合微载体来实现光穿孔促进的 siRNA 转染到单个细胞。因此，可以通过基于高通量的单细胞分析来对不同 siRNA 制剂进行随机基因沉默。为了筛选抗癌 siRNA 混合物，我们测试了 1300 多种 siRNA 组合，以敲低与肿瘤生长相关的多个基因，发现有效的 3-siRNA 制剂，重点是抑制 Cyclin D1 和存活素的关键作用，以及它们的协同效应互补靶标。这种方法将与大规模 siRNA 筛选相关的时间和成本减少了几个数量级，并解决了现有方法不允许的 siRNA 药理学的关键见解。