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

J Adv Res. 2026 Feb 18:S2090-1232(26)00177-3. doi: 10.1016/j.jare.2026.02.045. Online ahead of print.

ABSTRACT

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.

PMID:41720157 | DOI:10.1016/j.jare.2026.02.045