AT-RvD1 liposomes effectively accumulate in spinal cord and reprogram microglia via ANGPTL4-SUCLG1-propionate axis for treating neuropathic pain.

Neuropathic pain (NP) remains a major clinical challenge as current medications are ineffective in treating the underlying cause, and the clinical use of these drugs also has adverse reactions such as addiction. Therefore, specialized pro-resolving mediators (SPMs) may represent a promising therapeutic strategy. Microglia-mediated neuroinflammation is central to NP pathogenesis, yet feasible strategies for precise modulation of microglial inflammatory responses remain limited. Here, we reveal that aspirin-triggered resolvin D1 (AT-RvD1) promotes a shift of microglia toward an anti-inflammatory and pro-repair state via a novel ANGPTL4-SUCLG1-propionate axis, consequently attenuating neuroinflammation and pain hypersensitivity in mice models with NP. To address invasive nature of intrathecal injection limitation in NP clinical treatment, an MG1 peptide-modified liposomal delivery system encapsulating AT-RvD1 (AT-RvD1@Lipo-MG1) is developed. Intravenous administration of this nanoplatform enables effective and targeted delivery of AT-RvD1 to spinal microglia, with robust analgesic and anti-inflammatory effects and favorable biosafety in vivo. This study elucidates a novel mechanism through which AT-RvD1 modulates microglial inflammatory responses and proposes a highly translatable nanotherapeutic strategy for the treatment of NP.