Precise Spatiotemporal Control of Sensory Nerve Blockade via Light‐Triggered Click‐Release Uncaging of 2′,6′‐Pipecoloxylidide

The pursuit of non-opioid analgesics remains a critical priority in pain management. Local anesthetics (LAs) are promising alternatives to opioids, yet conventional agents indiscriminately block both sensory and motor fibers, leading to motor impairment. 2',6'-Pipecoloxylidide (PPX) has emerged as a sensory-selective LA, but its concentration-dependent activity requires precise local control that current delivery systems cannot achieve. Here, we report a red light (660 nm)-controlled liposomal platform that enables spatiotemporally precise release of PPX through a bioorthogonal photooxidation-click-release cascade. The system co-encapsulates a photosensitizer (chlorin e6), dihydrotetrazine (6-Pm-DHTz), and trans-cyclooctene-modified PPX (TCO-PPX). Upon 660 nm irradiation, 6-Pm-DHTz is oxidized to tetrazine, which rapidly reacts with TCO-PPX to liberate active PPX within minutes. In vitro studies confirmed rapid, controllable release, while in vivo experiments in a rat sciatic nerve model demonstrated reproducible, light-triggered sensory-selective nerve blockade without motor dysfunction. The duration and intensity of anesthesia were tunable by adjusting irradiation parameters, and delayed activation remained effective up to 8 h post-injection. The formulation exhibited excellent biocompatibility and prolonged local retention. This work establishes the first controllable platform capable of achieving purely sensory-selective local anesthesia, representing a conceptual and technological breakthrough toward programmable, personalized, and non-opioid pain therapy.