A wireless magnetoelectric-driven strategy to boost nose-to-brain drug delivery with сore-shell nanotransducers

Targeted therapeutic delivery to specific regions of the central nervous system (CNS) is a promising approach for treating localized pathologies such as neuropathic pain or viral infections. The systemic administration of drugs is often inefficient, as it distributes medication throughout the body, including non-targeted CNS areas, rather than concentrating it in the affected neural tissues. Leveraging axonal transport for targeted drug delivery could enable precise therapeutic interventions, such as antiviral, antineuropathic, or regenerative treatments, selectively directed to specific ganglia or CNS cells. In this study, we developed a novel strategy using magnetoelectric (ME) nanotransducers based on the core-shell MnFe₂O₄@Ba_0.85Ca_0.15Zr_0.1Ti_0.9O₃ nanoparticles (MFO@BCZT NPs), which exhibit an exceptionally high ME response (12.2 × 10⁵ mV·cm^-1·Oe^-1), to facilitated axonal transport of cargoes from the nasal cavity to the brain by a low-intensity alternating magnetic field (0-50 Hz, 0-30 mT). Firstly, in vitro experiments demonstrated that MFO@BCZT NPs efficiently activated voltage-gated calcium channels in primary neurons under safe magnetic stimulation. Ex vivo studies further confirmed enhanced cellular uptake of MFO@BCZT NPs and their ability for effective wireless stimulation of mouse hippocampal slices. Finally, in vivo experiments revealed significant ME-mediated improvement of axonal transport of BSA-Cy7 from nasal cavity into the mouse brain using MFO@BCZT NPs. This study establishes a non-invasive ME nanoplatform for spatiotemporally controlled neuronal logistics, offering a transformative approach for targeted therapeutic delivery to CNS.