Gut-to-brain nanoantenna-mediated in situ wireless charging activation across the brain barrier and neural regeneration

Abstract Gut-to-brain bioelectronic materials represents an emerging paradigm for non-invasive neuromodulation at brain. However, conventional carriers suffer from poor acid stability and limited permeability across intestinal epithelium and the blood–brain barrier (IEB and BBB). In this study, a transferrin (Tf)-coated conductive metal–organic framework antenna (Tf-cMOF) doubles as gut-to-brain ROS-scavenger and brain-penetrating enhancer for traumatic brain injury (TBI) treatment. Receptor-mediated transcytosis of Tf-cMOF allows therapeutics to be delivered across IEBs and reside in damaged TBI; the induced current generated by an external high-frequency magnetic field (HFMF) boosting permeability further promotes the particles-penetrating into TBI. The excellent intrinsic ROS-scavenging ability of Tf-cMOF, combined with the anti-inflammatory agent Probucol (P) loaded within it, effectively reduces inflammation during the early stage of TBI. In the secondary stage of TBI, under HFMF exposure, Tf-cMOF generates magnetoelectric coupling and local electric stimuli, promoting neuromodulation, neural differentiation and neural regeneration in both neural stem cells (NSCs) and in vivo. In vivo analyses further confirmed enhanced angiogenesis and neuronal infiltration around the TBI lesion, leading to functional recovery. This magnetoelectric Tf-cMOF demonstrates a promising route for gut-to-brain delivery of nano-antennas, establishing a versatile and wireless neuronal regeneration therapy.