Ultrasound-Assisted multimodal neuromodulation via nanosystems

Abstract Neuromodulation techniques have emerged as transformative tools for treating several neurological and psychiatric disorders, offering alternatives to traditional pharmacological approaches often hindered by the blood–brain barrier and off-target effects. While conventional modalities like deep brain stimulation, transcranial magnetic stimulation, and optogenetics have shown promise, they each face limitations in invasiveness, spatial resolution, or clinical applicability. In recent years, low-intensity ultrasound has gained attention as a noninvasive, deep-penetrating modality capable of modulating brain circuits with millimeter-sized spatial precision. This review explores the synergistic integration of ultrasound with engineered nanosystems to achieve multimodal neuromodulation such as electrical, mechanical, optical, and chemical via acoustic energy. We describe how nanoscale materials can transduce ultrasound into localized bioelectric signals, mechanical stress, light emission, or controlled drug release. These interactions enable precise, on-demand stimulation or inhibition of neuronal activity, including in deep brain regions. Experimental studies have demonstrated neuromodulatory effects across a variety of models, with applications ranging from optogenetics and drug delivery to behavioral modulation in rodents and primates. The review concludes with a critical assessment of the translational challenges such as nanoparticle delivery, biocompatibility, long-term clearance, and safety thresholds for human use while outlining promising strategies like cell-based delivery, biodegradable materials, and closed-loop control systems. These innovations highlight the potential of ultrasound-assisted nanosystems as transformative tools for precise neuromodulation in both experimental neuroscience and clinical applications. Graphical abstract