Spatial proteomic analysis of antimicrobial therapeutic-releasing intracortical probes as a platform technology to modulate specific neuroinflammatory pathways.

Intracortical microelectrodes (IMEs) remain limited by their inability to maintain stable neural recordings over time, largely due to a persistent and detrimental neuroinflammatory response to the implanted probe. One key event triggering this cascade is the disruption of the blood-brain barrier (BBB), which permits the translocation of gut-derived bacteria to the implant site and sustains chronic inflammation. To counter this, we previously engineered a titania nanotube array (TNA) coating for intracortical probes that significantly reduced microbial abundance at the implant interface. Bulk transcriptomic profiling revealed a marked decrease in neuroinflammatory gene activation in tissue surrounding the TNA-coated probes compared to uncoated controls. These findings suggest that TNA-coated probes may not only suppress microbial colonization but also directly attenuate host immune activation, offering a powerful new avenue to enhance chronic IME performance. In the present study, we extend this platform by leveraging the therapeutic-loading and controlled-release capacity of TNAs to further mitigate the remaining neuroinflammation at the implantation site. Cortical brain tissue from mice implanted with non-functional IMEs for 4 weeks was evaluated for neuronal integrity, immune cell activation, and local cytokine expression surrounding therapeutic-loaded TNA-coated probes using spatial proteomics to assess which side of the device the coatings are needed, to inform the future design of functional recording and stimulating probes. Our results indicate that TNAs provide a multifunctional, tunable interface, capable of locally modulating the neuroimmune microenvironment, which may enable long-term, reliable intracortical microelectrode probe recordings.