Upconversion Nanoparticles–Based Multiplex Protein Activation to Neuron Ablation for Locomotion Regulation

Abstract The optogenetic neuron ablation approach enables noninvasive remote decoding of specific neuron function within a complex living organism in high spatiotemporal resolution. However, it suffers from shallow tissue penetration of visible light with low ablation efficiency. This study reports a upconversion nanoparticle (UCNP)–based multiplex proteins activation tool to ablate deep‐tissue neurons for locomotion modulation. By optimizing the dopant contents and nanoarchitecure, over 300‐fold enhancement of blue (450–470 nm) and red (590–610 nm) emissions from UCNPs is achieved upon 808 nm irradiation. Such emissions simultaneously activate mini singlet oxygen generator and Chrimson, leading to boosted near infrared (NIR) light–induced neuronal ablation efficiency due to the synergism between singlet oxygen generation and intracellular Ca 2+ elevation. The loss of neurons severely inhibits reverse locomotion, revealing the instructive role of neurons in controlling motor activity. The deep penetrance NIR light makes the current system feasible for in vivo deep‐tissue neuron elimination. The results not only provide a rapidly adoptable platform to efficient photoablate single‐ and multiple‐cells, but also define the neural circuits underlying behavior, with potential for development of remote therapy in diseases.