Nano‐Anesthetics Regulate Neuro‐Immune Interaction for Treating Neuropathic Pain

Abstract Neuropathic pain is a multifaceted syndrome posing significant challenges to patient quality of life and healthcare systems. Conventional treatments primarily focus on general pain modulation, which fail to address specific underlying mechanisms, leading to limited efficacy and infinite side effects. Calcitonin gene‐related peptide (CGRP) has played a pivotal role in neuro‐immune repair, contributing to vasodilation, nociception, and immune modulation following tissue injury. Herein, a bupivacaine‐loaded cerium‐based metal–organic framework (CUB) is designed to integrate sustained release of analgesia with immunomodulatory and antioxidant capabilities. In vivo models of chronic constriction injury (CCI) have demonstrated that CUB significantly reduced neuroinflammation, promoted M2 microglial polarization, and enhanced myelin regeneration for the prolonged analgesia. Deep mechanism analysis revealed that the designed CUB can significantly elevate TSP‐1 expression to activate CGRP signal in modulating the neuro‐immune interaction, contributing to the repair process. Notably, the CUB outperformed standalone bupivacaine or cerium nanoparticles in terms of pain relief, motor function recovery, and neuroglial regulation. The findings highlight the potential of CUB as a multifactorial therapeutic for treating neuropathic pain, offering new perspectives on the integration of nanotechnology in chronic pain management through neuro‐immune pathways.