Targeted HA@Que-Mn nanozymes alleviate postherpetic neuralgia by modulating neuroinflammation

Postherpetic neuralgia (PHN), whose neuroimmune pathological mechanism remains unclear, is still an urgent clinical problem to be solved. In this study, we identified a key neurometabolic axis driving the occurrence of PHN, and developed a precise intervention strategy based on it. Cohort analysis based on the UK Biobank revealed that systemic inflammatory status was significantly associated with the risk of PHN. To translate this clinical association into actionable mechanistic targets, we integrated Mendelian randomization analysis with spinal cord transcriptomics data from a mouse PHN model, and found that functional deficiency of adenosine deaminase (ADA) was the core driver of the pro-inflammatory network. Mechanistic studies showed that specific downregulation of ADA expression in microglia led to pathological accumulation of local adenosine (ADO). Overloaded ADO broke the physiological analgesic homeostasis mediated by high-affinity A1/A3 receptors, and instead abnormally activated the low-affinity ADORA2B receptor pathologically upregulated in neurons, thereby triggering a neuroinflammatory cascade network that switched pain transmission from 'physiological analgesia' to 'pathological pro-inflammation'. Targeting this pathogenic pathway, we rationally designed a biomimetic nanozyme (HA@Que-Mn NPs). Through structure-oriented virtual screening, quercetin was selected as the conformational stabilizer of ADA; through manganese (Mn) coordination and surface functionalization with sodium hyaluronate (HA), the nanozyme was endowed with enhanced blood-brain barrier penetration ability, microglia-specific targeting and optimized catalytic efficiency of reactive oxygen species scavenging. In the resiniferatoxin (RTX)-induced mouse PHN model, systemic administration of the nanozyme effectively reshaped the neuroimmune microenvironment, inhibited pathological ADORA2B signal transduction, and achieved significant and long-lasting relief of neuropathic pain. This study established the ADA-ADO-ADORA2B pathogenic axis in PHN, and proposed a first-in-class nanozyme therapy with clinical transformation prospects, providing a new option for multi-omics driven targeted nanomedicine in the treatment of neuropathic pain.