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.

Control of Luminescence and Interfacial Properties as Perspective for Upconversion Nanoparticles

“…With optogenetic approaches using UCNPs, it was already possible to achieve locomotion control in C. elegans, which changed their direction under 980 nm irradiation [97] or manipulation of the food intake behavior of mice, as recently demonstrated by Zhong et al [98] Zhang et al presented a strategy that is elegant in both, the particle architecture as well as their application to neural manipulations (Figure 6b). They fabricated UCNPs with a total of seven shells, resulting in particles that are excitable at three different wavelengths (1532/808/980 nm) and exhibit trichromatic green, red, and blue emissions.…”

Emerging optogenetics technologies in biomedical applications

“…[86][87][88] For instance, UCNPs have been used to convert high-penetrating, low-energy near-infrared light into high-energy visible light or fluorescence, which is sufficient to excite voltage-gated channels and generate action potentials. [89][90][91][92] Additionally, photothermal nanoparticles, such as gold nanoparticles (AuNPs), can convert light into heat energy and drive heat-induced promoters to drive downstream signal expression. 93,94 Other nanoparticles, including mechanoluminescent and radioluminescent nanoparticles, have also been widely studied.…”

Unrestricted molecular motions enable mild photothermy for recurrence-resistant FLASH antitumor radiotherapy

“…Photothermal technology is promising in modern medicine and can be used in various fields such as smart drug delivery [ 26 , 27 ], antitumor therapy [ 28 , 29 ], infection treatment [ 30 ], and neural modulation [ [31] , [32] , [33] ]. Photothermal agents with strong absorption in the near-infrared window (NIR, 650–1700 nm) are attractive because they can be excited deeply inside the biological tissues [ 31 , 34 ].…”