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

ABSTRACT 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.