Sustained Relief of Chronic Pain via a Nav1.7-Targeting ASO–siRNA Conjugate

SUMMARY Chronic pain affects billions globally, yet safe, long-lasting, and non-addictive analgesics remain lacking. Nav1.7 is a genetically validated pain target, but traditional small molecules have repeatedly failed. Therapeutic oligonucleotides-antisense oligonucleotides (ASOs) and siRNAs-offer selective, durable silencing. We developed N02C0702, an ASO-siRNA conjugate (ASC), achieving robust Nav1.7 knockdown and sustained analgesia without additional delivery vehicles. N02C0702 outperformed individual ASO (N02A114) and siRNA (N02S154) moieties at mRNA and protein levels and in pain relief. In CFA-induced inflammatory pain, a single intrathecal dose exceeded naproxen and suzetrigine, while in SNL neuropathic pain, efficacy persisted up to 56 days, comparable to or surpassing pregabalin. Genome-wide RNA sequencing confirmed minimal off-target effects. N02C0702 highlights Nav1.7 as a key analgesic target and demonstrates the ASC platform’s potential for chronic pain and other CNS-related pathologies, offering durable, selective, and safe therapeutic effects.