Doping-Induced Assembly Interface for Non-Invasive In Vivo Local and Systemic Immunomodulation

Peripheral neural interfaces exhibit considerable potential in the treatment of diseases by modulating both local and systemic immune responses. However, the mismatch between static electronic components and the dynamic, intricate tissue organization of the peripheral nervous system results in interface failure, hindering progress in circuit research and clinical implementation.<br/><br/>Jet-injectors are preferred by diabetic patients for insulin administration over syringes due to their enhanced diffusivity and reduced scar formation. By leveraging the diffusivity of jet-injection and in vivo polymerized neural interfaces, we aim to interface with the finely structured reticular nerve plexus, which has been demonstrated to possess unique capabilities in peripheral-central circuitry, such as systemic anti-inflammation, anxiety, and social disorders. However, recent in vivo polymerization systems are incompatible with this inherently diffusion-promoting injection method, as precursors, enzymes, and surfactants diffuse into the tissue and ultimately hinder the polymerization process.<br/><br/>To address these challenges, We developed a versatile, monocomponent cocktail strategy for the in vivo assembly of biodegradable, self-adaptive neural interfaces to achieve both local and global immunomodulation. To accomplish this regulation, we employed a propulsionary flow-enhancing method—jet-injection—to interface with a series of reticular nerve plexuses. Additionally, we engineered ROS-triggered catalytic doping nanosheets with inherently low diffusivity to counteract tissue diffusion during jet-injection. MXene, a semi-metal, has been extensively investigated for its conductivity and catalytic properties. We harnessed MXene's catalase activity to catalyze the in vivo doping system, reconciling the conflict between catalyst and conductivity. Furthermore, we functionalized MXene with de-doped conductive polymer (CP)–PEDOT and dopant–benzenesulfonic acid. The doping of de-doped PEDOT is mediated by the ROS-MXene cascade, which occurs when the injection induces local microdamage, increasing ROS metabolites in tissue and subsequently triggering PEDOT doping by MXene. This doping process enhances the π-π interaction between nanosheets, driving in vivo assembly. Additionally, we employed a tissue cross-linking compound, PDA, to connect de-doped PEDOT and benzenesulfonic acid dopant, controlling spontaneous non-catalytic doping. This approach also allows nanosheets to form dynamic bonds during assembly, including hydrogen bonds, coordination bonds, cation–π interactions, and π–π interactions, further reducing diffusion.<br/><br/>Our neural interface can be deployed within 10 seconds, and the π-π mediated assembly process, along with the metabolic oxidation of MXene, enables biodegradation of the interface. The neural interface, established with the sciatic nerve, can promote peripheral tissue recovery through local regulation via electrical stimulation. In freely moving mice, the neural interface activated the vagal anti-inflammatory axis at ST36, releasing noradrenaline, adrenaline, and dopamine from adrenal chromaffin cells while reducing TNF and IL-6 levels in serum. We demonstrate that catalytic doping and cross-linking around peripheral tissue create degradable, self-adaptive interfaces with reticular nerve plexuses in peripheral-central circuitry.