Optogenetic Control of Non‐Apoptotic Cell Death

Herein, a set of optogenetic tools (designated LiPOP) that enable photoswitchable necroptosis and pyroptosis in live cells with varying kinetics, is introduced. The LiPOP tools allow reconstruction of the key molecular steps involved in these two non‐apoptotic cell death pathways by harnessing the power of light. Further, the use of LiPOPs coupled with upconversion nanoparticles or bioluminescence is demonstrated to achieve wireless optogenetic or chemo‐optogenetic killing of cancer cells in multiple mouse tumor models. LiPOPs can trigger necroptotic and pyroptotic cell death in cultured prokaryotic or eukaryotic cells and in living animals, and set the stage for studying the role of non‐apoptotic cell death pathways during microbial infection and anti‐tumor immunity. A new class of genetically‐encoded actuators, designated LiPOPs, are designed to enable photoswitchable necroptosis or pyroptosis. LiPOPs are coupled with upconversion nanoparticles (UCNPs) or NanoLuc‐mediated luminescence‐aided optogenetic stimulation (NanoLOGS) to achieve wireless nano‐optogenetic or chemo‐optogenetic control of cell death in vivo with superior spatiotemporal precision. LiPOPs can also be exploited as safety switches to facilitate the development of safer cell‐based therapies.