Gold Nanoparticle-BasedNear-Infrared PhotothermalModulation of TRPV1 Activation in Glial Cells

Abstract The transient receptor potential vanilloid 1 (TRPV1) channel is a heat-sensitive nonselective cation channel mediating the influx of calcium (Ca2+) and sodium (Na+) ions upon activation, leading to membrane depolarization, generation of action potential, and downstream signaling cascades. TRPV1 plays a crucial role in thermal homeostasis, neuronal excitability, and intracellular calcium dynamics, positioning it as a compelling target for therapeutic interventions in neurological disorders. Moreover, on-demand opening of a heat-sensing TRPV1 channel in response to exposure to an elevated temperature has led to the emergence of thermogenetics, as a transformative technology enabling control over neuronal signaling. Thermogenetics has already impacted biomedical research; however, its immense potential for clinical care has not yet been realized. A key challenge in thermogenetics is precisely localized heat generation, which continues to limit its therapeutic use. To address this limitation, TRPV1 receptors have been targeted with nanoparticles to absorb IR irradiation, locally dissipate heat, and activate TRPV1 channel opening. However, suboptimal photothermal efficiency is a predicament encountered in such simulations, which limits prospective clinical applications. In this study, we prepared TRPV1-targeting, chitosan-coated gold nanospheres (TRPV1-Au NS) and gold nanorods (TRPV1-Au NR) for comparative analysis of thermal stimulation and subsequent calcium influx. This approach demonstrated high precision of targeting TRPV1 channels enabling activation in subcellular regions of interest and achieving high temporal resolution relevant for studies of neuronal signaling. Our experiments demonstrate a thermoplasmonic platform in which TRPV1-Au NR produced larger and more sustained calcium fluorescence responses than TRPV1-Au NS under the respective irradiation conditions used for each formulation. The local temperature was not directly measured, and the results therefore represent a comparison of functional calcium responses rather than direct photothermal conversion efficiencies. These findings contribute to the ongoing development of high-precision photothermal nanotherapeutics.