Phase-tunable lyotropic liquid crystals with low viscosity and improved safety for long-acting local anesthesia.

The short half-life of local anesthetics often hinders postoperative pain (POP) management, as repeated or high-dose administration elicits risks of severe systemic toxicity and nerve fiber damage. While in-situ lyotropic liquid crystals (LLCs) hold promises as sustained-release depots, their clinical translation is affected by high viscosity and irritating solvents. To overcome these critical barriers, we developed a novel liquid crystal forming system (LCFS) driven by a strategic molecular design. By introducing diethylene glycol monoethyl ether (DGME) into phosphatidylcholine (PC) and adding low-viscosity stabilizers such as lauric acid monoester and propane-1,2-diol (LAMP), we successfully formed a low viscosity LCFS. This structurally optimized LCFS exhibits good needle passability before rapidly undergoing a water-triggered phase transition into highly ordered inverse hexagonal (HII) or cubic (Pn3m) nanostructures, creating a diffusion-regulating matrix. Notably, the HII and Pn3m nanostructures allow for compositional phase control to modulate release behavior, demonstrating prolonged in vitro release durations. In vivo evaluations demonstrated that a single injection of Bupivacaine-loaded LCFS delivered robust, continuous analgesia for rigorous pain models. Crucially, this depot maintained a flat pharmacokinetic profile. By adjusting the components, this LCFS establishes a translatable, next-generation platform for ultra-long-acting POP management.