A "Cell Space Station" for Spatiotemporal Molecular Manipulation of Immune Checkpoint

Spatiotemporal manipulation of protein distributions, abundances, and functions based on molecular level remains a significant challenge in studying biological systems and developing therapeutics. Particularly, such a nanotherapeutic platform though both specific and internal way is extremely lacking. Herein, we put forward a click chemistry-driven protein sorting (PROCLISORT) strategy, which acted in a cell space station (CSS) to achieve the sequential regulation of specific protein along the entire PD-1 immune checkpoint axis. From the spatial dimension, CSS could achieve comprehensive recognition, anchoring and blocking PD-L1/PD-L2 as well as transport PD-L1 among organelles at the subcellular level. From the time dimension, through the booting control via click reaction, the occurrence of these biological regulatory events became controllable and sequential, thus resulting in rapid and durable down-regulation of PD-L1. Through these smart tasks, this CSS stimulated a satisfactory tumor-immune-therapy effect both in vitro and in vivo. With a rational design, this multistage booting nanoplatform holds promise for molecular manipulation along the disease-related pathway in various living systems.