Abstract：
Immune checkpoint protein blockade (ICB) has emerged as a powerful immunotherapy approach, but suppressing immune-related adverse events (irAEs) for noncancerous cells and normal tissues remains challenging. Activatable ICB has been developed with tumor microenvironment highly-expressed molecules as stimuli, but they still lack precision and efficiency considering the diffusion of stimuli molecules in whole tumor tissue. Here we assemble PD-L1 with a duplex DNA strand, termed as \"safety catch\", to regulate its accessibility for ICB. The safety catch remains at \"on\" status for noncancerous cells to prevent ICB binding to PD-L1. Cancer cell membrane protein c-Met acts as a trigger protein to react with safety catch, which selectively exposes its hybridization region for ICB reagent. The ICB reagent is a retractable DNA nanostring with repeating hairpin-structural units, whose contraction drives PD-L1 clustering with endocytosis-guided degradation. The safety catch, even remained at \"safety on\" status, is removed from the cell membrane via a DNA strand displacement reaction to minimize its influence on noncancerous cells. This strategy demonstrates selective and potent immunotherapeutic capabilities only against cancer cells both in vitro and in vivo, and shows effective suppression of irAEs in normal tissues, therefore would become a promising approach for precise immunotherapy in mice.
摘要：
免疫检查点蛋白阻断（ICB）已成为一种强大的免疫治疗方法，但抑制非癌细胞和正常组织的免疫相关不良事件(irAEs)仍然具有挑战性.以肿瘤微环境高度表达的分子为刺激，开发了可激活的ICB，但是考虑到刺激分子在整个肿瘤组织中的扩散，它们仍然缺乏精确性和效率。这里我们用双链DNA链组装PD-L1,被称为“安全捕获”，规范其对ICB的可及性。非癌细胞的安全捕获保持在“开启”状态，以防止ICB与PD-L1结合。癌细胞膜蛋白c-Met作为触发蛋白与安全捕获反应，选择性地暴露其用于ICB试剂的杂交区域。ICB试剂是一种可伸缩的DNA纳米串，具有重复的发夹结构单元，其收缩驱动PD-L1聚类，内吞引导降解。安全捕捉，甚至保持“安全开启”状态，通过DNA链置换反应从细胞膜上去除，以最大程度地减少其对非癌细胞的影响。该策略显示了仅在体外和体内针对癌细胞的选择性和有效的免疫治疗能力。并显示对正常组织中的irAE的有效抑制，因此将成为小鼠精确免疫疗法的一种有希望的方法。
