Long-term sciatic nerve block led by a supramolecular arrangement of self-delivery local anesthetic nano systems

Classical local anesthetics are unsuitable to treat regional pain lasting several days due to their limited duration and systemic toxicity. Self-delivery nano systems without excipients were designed for long-term sensory blocks. 1a self-assembled into different vehicles with different fractions of intermolecular π-π stacking, transported itself into nerve cells, and released single molecules slowly to achieve long-term duration for rats' sciatic nerve block for 11.6 h in water, 12.1 h in water with CO₂ and 3.4 h in NS (normal saline). After the counter ions were changed to SO₄^2-, 1e can self-assemble into vesicles and prolong the duration to 43.2 h, which was much longer than the 3.8 h led by (s)-bupivacaine hydrocloride (0.75%). This was mainly caused by the enhancement of self-release and counter ion exchange inside nerve cells, which were affected by the gemini surfactant structure, pK_a of the counter ions and π-π stacking interactions.