NIR-II Neuromodulation Combined with Metabolite-Mediated Immunoregulation for Accelerated Deeply Located Nerve Repair

Deep peripheral nerve regeneration is hindered by inflammatory infection, neurotrophic factor deficiency, and slow axonal growth kinetics. Although multifunctional nerve guidance conduits (NGCs) have been developed, achieving spatiotemporally precise neuromodulation within deeply located neural tissues remains a significant challenge. Herein, we developed a nerve conduit fabricated with a gut metabolite indole-3-propionic acid (IPA)-functionalized and polydopamine-coated Au nanorod clusters (AuNR@PDA-IPA (API)) loaded on a parallel fiber film of PLGA, exhibiting NIR-II-responsiveness for spatiotemporally precise neuromodulation. API nanoclusters convert deep-penetrating NIR-II light (1064 nm wavelength) into deeply localized heat (∼42-43 °C), which noninvasively activates the transient receptor potential vanilloid 1 (TRPV1) channel in Schwann cells (SCs). This activation triggers Ca²⁺ influx and membrane depolarization, promoting neurotrophic expression. Concurrently, NIR-II irradiation directly modulated the release of neuroprotective IPA from the API platform through an on-off switching mechanism. Meanwhile, IPA combined with PDA potently scavenged reactive oxygen species (ROS), suppressed NF-κB activation, and promoted M2 polarization of macrophages, thereby reshaping the neuroregenerative microenvironment. The in vitro and in vivo results demonstrate that API-functionalized conduit enhances VEGF-driven angiogenesis and activates SCs to upregulate the expression of neurotrophic factors (BDNF, NGF) and glial-specific proteins (S100, GFAPs). By orchestrated tripartite regulation of the "anti-inflammatory-angiogenic-neuroregenerative" system, the conduit enabled robust axonal regrowth, remyelination, and functional recovery in peripheral nerve defects, offering a transformative strategy for the repair of deeply located neural tissues. This work presents a noninvasive bioelectronic paradigm that merges spatiotemporal photothermal neuromodulation with immune metabolic reprogramming for precision neural reconstruction.