Noninvasive Manipulation of Ion Channels for Neuromodulation and Theranostics

Abstract

ConspectusFunctional and structural studies of ion channels have deepened our understanding of their mechanisms and important role in regulating neuronal activity and treating disease. Manipulation of ion channels can directly control electrochemical signals in the nervous and cardiovascular systems for advanced neuromodulation and theranostics. Manipulation tools based on ion channel control, such as optogenetics, electrical stimulation, chemogenetics, and gene editing, have advanced basic biomedical research and enabled unprecedented treatment strategies. Nevertheless, conventional approaches are associated with limitations such as invasiveness, irreversibility, or low spatiotemporal resolution, which limit their clinical application. Therefore, targeted noninvasive or minimally invasive modulation of various ion channel activities is highly desirable.In recent years, nanomaterials have enabled noninvasive and precise modulation of ion channels due to their tunable morphology and physicochemical properties. Based on activation modes, current nanomaterial-based methods for ion channel control include light stimulation, thermal regulation, and mechanical manipulation. Nanomaterials can serve as energy transducers to convert macroscopic signals that penetrate deep into tissue, such as near-infrared light or magnetic fields, into local stimuli for ion channel manipulation. For photomodulation, lanthanide-doped nanoparticles convert near-infrared light into visible energy by upconversion, enabling bidirectional control of excitatory and inhibitory opsins in deep tissues. For thermal modulation, photothermal nanoparticles transform absorbed light, such as near-infrared, into heat to activate thermosensitive channels in deep targets. For mechanical manipulation, magnetic nanoparticles convert external magnetic fields into local attractive and torque forces to regulate the functionality of mechanosensitive channels without concern for penetration depth. Moreover, nanomaterial-based strategies can realize targeted and minimally invasive control over the activities of various ion channels even at the single-cell level, maximizing their feasibility and application potential.In this Account, we focus on the manipulation of ion channels using nanomaterials and categorize current approaches into photoconversion optogenetics, thermogenetics, and magnetogenetics. We first introduce the biological principles of various opsins, discuss thermo- and mechanosensitive ion channels and describe their molecular mechanisms in the context of channel structures. We also outline the general principles of emerging nanomaterials in terms of energy conversion capability. We highlight the major advances in nanoprobe-enabled systems and their modern applications in neuromodulation and theranostics. We conclude the Account with a discussion of existing challenges and future prospects.