Ferrimagnetic Vortex Nanorings Facilitate Efficient and Safe Deep-Brain Magnetothermal Stimulation in Freely Moving Mice

Magnetothermal neuromodulation is a minimally invasive, deep-brain accessible, and tether-free technique. The precisely timed activation of thermosensitive ion channels, such as TRPV1, with local heat generated using magnetic nanoparticles is crucial for efficient neuromodulation. Nevertheless, this technique is greatly hindered by its long stimulus-response time and high safety risks due to the poor heat-generating performance of the nanomediators. Herein, we report the establishment of a ferrimagnetic vortex iron oxide nanoring (FVIO)-mediated magnetothermal neurostimulation technique that is efficient and safe. Compared with widely used superparamagnetic iron oxide nanomediators (SPIOs), the FVIOs triggered Ca²⁺ influx into HEK293T cells and cortical neurons at an Fe concentration of 51 µg mL⁻¹, which is 20.27-fold lower than that needed for SPIOs. In vivo magnetothermal stimulation in the central nucleus of the amygdala of mice further demonstrated that FVIOs with the optimal dose of 0.05 µg evoked fear behaviors with an average latency of 2.51 s, which was 2.3-fold faster than that in the SPIO (0.80 µg)-treated group. More importantly, FVIOs-mediated stimulation not only exhibited negligible histopathological alterations and proinflammatory cytokine expression but also successfully elicited fear behaviors in transgene-free mice. The FVIO-mediated efficient and safe neuromodulation has the potential for future neuroscience exploitation and neurological disease treatment.