Injectable Poloxamer and Hyaluronic Acid Hydrogel for Sustained Co-Delivery of Dexamethasone and Lidocaine Ameliorates Neuropathic Pain.

Neuropathic pain is a debilitating condition driven by complex neuro-immune-glial interactions and central sensitization. Current pharmacological interventions, such as opioids and ion channel blockers, are often limited by short half-lives, systemic toxicity, and tolerance. To overcome these barriers, we developed an injectable, thermosensitive hydrogel system based on poloxamer and hyaluronic acid (PLX/HA) for the sustained, localized co-delivery of dexamethasone (Dex) and lidocaine (Lid). In vitro characterization demonstrated that HA incorporation optimized the hydrogel's microstructural porosity, enabling the sustained release of bioactive agents for up to 28 d. At the cellular level, the system marked enhanced neuronal survival under inflammatory stress by modulating the Bax/Bcl-2 apoptotic pathway and suppressing nuclear factor κB (NF-κB) nuclear translocation and cyclooxygenase-2 (COX-2) expression. In a rat model of chronic constriction injury (CCI), the Dex/Lid@PLX/HA formulation provided sustained improvement in mechanical allodynia and thermal hyperalgesia, with greater efficacy than the solution and standard gel control groups at multiple time points. Mechanistically, the therapeutic effects were accompanied by attenuation of TRPV1, CGRP, and SGC activation-related signals, suggesting suppression of peripheral nociceptive sensitization and attenuation of DRG neurodegenerative pathology, including reduced Nageotte nodule-like changes. Furthermore, the PLX/HA system was associated with reduced proinflammatory macrophage infiltration and an increased CD163-positive macrophage signal, suggesting a more reparative local immune microenvironment. This study presents a localized co-delivery strategy with analgesic and anti-inflammatory effects for neuropathic pain management and peripheral nerve protection.