Lipid nanoparticle-mediated Cd14 siRNA delivery ameliorates the acute inflammatory response to intracortical microelectrode implantation.

Intracortical microelectrodes (IMEs) are an integral component of brain computer interfaces (BCIs) designed to study and treat neurological disorders. Unfortunately, IMEs tend to fail prematurely due in part to the macrophage-mediated inflammation in response to implantation injury and the persistent foreign body reaction. Previous work has established that cluster of differentiation 14 (CD14) is implicated in the neuroinflammatory response to IME implants. CD14 is a conserved damage-associated coreceptor that facilitates immune activation in the presence of inflammatory damage-associated stimuli. We sought to mitigate the inflammatory response to IME implantation by suppressing CD14 expression on macrophages using a lipid nanoparticle (LNP) loaded with Cd14-specific siRNA. We tested the efficacy of the LNP-mediated gene delivery in cultured murine macrophages and in an in vivo mouse model with IME implants. Our in vitro findings indicated that the LNPs suppress inflammatory cytokine secretion. The in vivo studies showed efficient targeting of the LNPs to the desired cell populations with the majority of LNPs found in blood-circulating macrophages and infiltrating macrophages at the intracortical implant site. Our results show that the LNPs efficiently silence expression of the targeted Cd14 gene. Suppression of the CD14 protein led to reduced infiltration of immune cells to the brain parenchyma, as well as a significant decrease of the inflammatory response to implantation within the first 24 h after implantation, as determined by flow cytometry and transcriptomics. Together our results suggest that LNP-mediated gene therapy can specifically regulate one of the dominant drivers of the innate immune response to IME implantation. STATEMENT OF SIGNIFICANCE: Brain-computer interfaces rely on implanted electrodes to record and stimulate neural activity, but these devices often fail early because the body mounts an inflammatory immune response against them. Here, we focused on a central immune receptor, CD14, as a key driver of the inflammatory response to implants. Using lipid nanoparticles to deliver gene-silencing RNA, we were able to suppress CD14 expression in macrophages both in culture and in a mouse model with implanted electrodes. This targeted approach reduced immune cell infiltration and inflammation around implants. Our findings demonstrate that lipid nanoparticle-mediated gene therapy can selectively weaken the brain's innate immune response to implants, offering a promising strategy to improve the longevity and performance of neural interfaces.