Dual Behavior Regulation: Tether‐Free Deep‐Brain Stimulation by Photothermal and Upconversion Hybrid Nanoparticles

Abstract Optogenetics has been plagued by invasive brain implants and thermal effects during photo‐modulation. Here, two upconversion hybrid nanoparticles modified with photothermal agents, named PT‐UCNP‐B/G, which can modulate neuronal activities via photostimulation and thermo‐stimulation under near‐infrared laser irradiation at 980 nm and 808 nm, respectively, are demonstrated. PT‐UCNP‐B/G emits visible light (410–500 nm or 500–570 nm) through the upconversion process at 980 nm, while they exhibit efficient photothermal effect at 808 nm with no visible emission and tissue damage. Intriguingly, PT‐UCNP‐B significantly activates extracellular sodium currents in neuro2a cells expressing light‐gated channelrhodopsin‐2 (ChR2) ion channels under 980‐nm irradiation, and inhibits potassium currents in human embryonic kidney 293 cells expressing the voltage‐gated potassium channels (KCNQ1) under 808‐nm irradiation in vitro. Furthermore, deep‐brain bidirectional modulation of feeding behavior is achieved under tether‐free 980 or 808‐nm illumination (0.8 W cm−2) in mice stereotactically injected with PT‐UCNP‐B in the ChR2‐expressing lateral hypothalamus region. Thus, PT‐UCNP‐B/G creates new possibility of utilizing both light and heat to modulate neural activities and provides a viable strategy to overcome the limits of optogenetics.