Prussian blue nanozymes alleviate postoperative pain via upregulating endogenous SMOC2 secretion in dorsal root ganglion fibroblasts

• PB nanozymes provide sustained relief of postsurgical mechanical pain • Analgesic effect mediated by fibroblast-derived SMOC2 in DRG. • PB nanozymes modulate extracellular matrix pathways without toxicity. • Smoc2 knockdown abolishes PB nanozyme–induced pain relief. • Bioactive nanomaterials enable endogenous analgesia in situ . • Provides a non-opioid strategy with strong translational potential. Introduction : Postoperative pain remains clinically challenging, and non-opioid strategies are needed. Fibroblast-derived secreted modular calcium-binding protein 2 (SMOC2) in the dorsal root ganglion (DRG) suppresses mechanical pain, offering a potential endogenous target. Objectives : This study aimed to develop a non-opioid analgesic strategy by using Prussian blue nanozymes (PBzymes) to stimulate the in situ secretion of endogenous SMOC2 from DRG fibroblasts, an approach designated here as “endogenous analgesia.” Methods : PBzymes were synthesized and characterized. A mouse plantar incision model was used to assess pain behavior, supplemented with 3D-motion analysis, DRG transcriptomics, molecular assays, and whole-cell patch-clamp recording. SMOC2 necessity and sufficiency were tested via DRG-specific knockdown and intrathecal SMOC2 administration, respectively. Fibroblast secretion and preliminary safety were also evaluated. Results : A single peripheral injection of PBzymes (75 µg/mL) produced sustained attenuation of incision-induced mechanical allodynia, without affecting thermal hyperalgesia. PBzyme treatment reduced DRG neuron hyperexcitability, reflected by a hyperpolarized resting membrane potential and an increased action potential threshold. Transcriptomic analysis revealed upregulation of extracellular matrix-related genes, including Smoc2, which was confirmed at mRNA and protein levels in DRG tissues and in cultured fibroblasts. PBzymes enhanced SMOC2 secretion without cytotoxicity. DRG-specific Smoc2 knockdown abolished PBzyme-induced analgesia and the associated electrophysiological improvements, whereas exogenous SMOC2 administration recapitulated the analgesic effect. No adverse effects on body weight or major organ histology were observed. Conclusion. This work establishes an “endogenous analgesia” strategy in which PBzymes alleviate postoperative mechanical pain by upregulating fibroblast-derived SMOC2 in the DRG. Evidence from loss-of-function, gain-of-function, and functional electrophysiological studies supports a central role for SMOC2 in this mechanism. The approach presents a promising, sustained, non-opioid avenue for pain management.