Metformin Nanodelivery System Alleviates Morphine-Induced Analgesic Tolerance via Inhibiting the TXNIP/NLRP3/GSDMD Axis.

Morphine-induced analgesic tolerance limits its clinical use. This study shows that metformin alleviates such tolerance by inhibiting the TXNIP/NLRP3/GSDMD axis, reducing microglial activation and proinflammatory cytokines in CD-1 mice (metformin 200 mg/kg i.p.; morphine 10 mg/kg s.c.) and BV-2 cells (metformin 100 μM; morphine 200 μM). TXNIP is critical, as its overexpression weakens metformin's effect. The TXNIP siRNA/metformin coloaded TM@ZIF-8/HA nanosystem enhances efficacy via pH-responsive, CD44-targeted delivery with good biocompatibility, providing a perioperative pain management strategy.