Injectable thermosensitive lidocaine hydrogel for on-demand postoperative analgesia and cancer–nerve crosstalk suppression

• Thermosensitive liposome hydrogel enables on-demand, sustained pain relief.. • External ice application precisely triggers lidocaine release for controlled analgesia. • Inhibits cancer–nerve interactions, reducing risk of recurrence and metastasis. Postoperative pain management and tumor recurrence remain major challenges in cancer surgery, with few strategies addressing both simultaneously. Here, we report a thermosensitive, in situ-forming hydrogel system (POIL) composed of lidocaine-loaded liposomes embedded in a Pluronic F127 matrix for dual-function postoperative therapy. The POIL hydrogel exhibited a sol–gel transition, which enabled localized gelation upon minimally invasive injection. When administered around the sciatic nerve or applied to the postoperative tumor resection site, the POIL provided sustained release of lidocaine over four days. Additionally, ice packing triggered a burst release of lidocaine by lowering the local temperature, thereby enabling on-demand pain relief. In vivo studies confirmed that repeated application of ice packs prolonged the analgesic effect of POIL to more than 100 h and reduced the expression of pro-inflammatory cytokines in muscle tissues, without causing significant tissue toxicity. Furthermore, the released lidocaine inhibited Schwann cell migration and suppressed interactions between cancer cells and nerve fibers by downregulating NGF expression in the tumor microenvironment. These effects contributed to the effective prevention of postoperative tumor recurrence and metastasis in 4 T1 tumor-bearing mice. These results demonstrated the clinical potential of POIL as a patient-controllable hydrogel system for simultaneous pain management and cancer recurrence prevention.