α‑Lipoic Acid-Based Wet-Adhesive Supramolecular Powder Promotes Oral Mucosa Healing by Inhibiting NF-κB Signaling.

Abstract

Oral mucosal lesions present significant therapeutic challenges due to the complex oral environment and the limitations of conventional biomaterials in clinical application. Herein, a self-gelling supramolecular powder composed of polyethyleneimine (PEI), poly (acrylic acid) (PAA), and α-lipoic acid (LA) is developed for oral ulcer management. Upon contact with saliva, the powder rapidly absorbs water and undergoes instantaneous self-gelation (<5 s), forming a physically cross-linked hydrogel that exhibits robust wet adhesion to oral mucosal tissues. The incorporation of LA enhances the mechanical integrity of the network without increasing swelling, while enabling sustained LA release that imparts intrinsic anti-inflammatory bioactivity. In a murine oral ulcer model, the optimized PEI/PAA/1%LA formulation accelerates wound healing, reduces pain-associated behaviors, and suppresses local expression of IL-1β and TNF-α. Mechanistically, transcriptomic analysis reveals that LA exerts its anti-inflammatory effects through comprehensive suppression of both classical and noncanonical NF-κB signaling pathways, downregulating Nfkb1, Nfkb2, and downstream inflammatory cytokines. By integrating durable wet adhesion with controlled therapeutic delivery, this supramolecular system offers a clinically translatable strategy for oral mucosal regeneration that addresses both biological healing requirements and patient comfort.