Balancing stability and cleavability of magnetoelectric nanovesicles for wireless and noninvasive deep brain stimulation in epilepsy therapy

Polymeric vesicles hold considerable promise as noninvasive delivery platforms for magnetoelectric nanoparticles (MENPs). This strategy enables wireless and noninvasive neural stimulation and offers effective therapeutic avenues for epilepsy, representing a translatable bench-to-bedside pathway for deep-brain magnetoelectric stimulation. However, polymer vesicles have not been widely explored for delivering MENPs in neurostimulation. A key challenge is balancing the structural stability of magnetoelectric vesicles during delivery with their rapid, on-demand cleavage at the target site, which is particularly paramount and challenging for epilepsy treatment. It is conceivable that the ROS-cleavable design could, in principle, contribute to a more localized stimulation profile and potentially help mitigate off-target effects. Following vesicle disruption, the slow release of MENPs might, under favorable conditions, result in some reduction of polymeric charge shielding, which could conceivably have a bearing on magnetoelectric stimulation performance. Amorphous bottlebrush poly(D,L-lactic acid)-dextran (PDLLA-Dextran) vesicles were developed with systemic delivery stability, and their ROS-responsive cleavage capacity may be preliminarily considered as one possible factor that could influence the spatial distribution of MENP release. Prussian blue staining confirmed their preferential accumulation in inflammatory hippocampal and cortical regions as distinct microclusters, which enhanced magnetoelectric transduction. Electroencephalography and c-Fos mapping demonstrated significant suppression of pathological network hypersynchrony in epileptic rats. These vesicles offer a versatile strategy for wireless, noninvasive neuromodulation, with significant translational potential for deep-brain stimulation therapies in epilepsy and related neurological disorders. STATEMENT OF SIGNIFICANCE: About one-third of focal epilepsy patients don't respond to medication, and current deep-brain stimulation implants or injections are invasive and imperfectly targeted. MENPs provide wireless electrical stimulation powered by external magnetic fields; however, their limited colloidal stability and constrained spatial control have impeded their clinical translation. We introduce amorphous bottlebrush PDLLA-dextran vesicles that stabilize MENPs during systemic delivery yet rapidly disassemble in reactive-oxygen-species (ROS)-rich epileptic microenvironments. This design addresses a critical trade-off between circulation stability and stimulus-responsive release, thereby facilitating more comprehensive MENP exposure for enhanced magnetoelectric charge generation under an external magnetic field. The platform promotes minimally invasive, targeted neuromodulation and may be broadly applicable for deep-brain disorders where local inflammation can inform on-demand activation.