pH-responsive hydrogel facilitates skin penetration of extracellular vesicle-like nanovesicles for enhanced atopic dermatitis therapy

Atopic dermatitis (AD) is a chronic inflammatory skin disorder, and the long-term use of topical corticosteroids is often limited by adverse effects and poor tolerability. Herein, we developed CAAM-G, a corticosteroid-free hydrogel platform composed of carboxymethyl cellulose, acrylamide, and acrylic acid and loaded with Gentiana macrophylla Pall.-derived extracellular vesicle-like nanovesicles (GELNs) and L-menthol. The hydrogel exhibited favorable mechanical properties, tissue adhesion, and swelling capacity. Under mildly to moderately alkaline conditions relevant to lesional AD skin, it exhibited pH-dependent release of GELNs and menthol. The released menthol enhanced the cutaneous distribution of PKH26-labeled GELN-associated fluorescence in a porcine skin Franz diffusion model. In vitro, GELNs-containing formulations efficiently scavenged reactive oxygen species (ROS), suppressed pro-inflammatory cytokine secretion, and promoted macrophage polarization toward an M2-like phenotype. In the DNFB-induced AD-like mouse model, the high-dose formulation, CAAM-GH, significantly alleviated ear swelling, epidermal thickening, mast cell infiltration, and other AD-like manifestations. For several evaluated endpoints, CAAM-GH produced greater improvement than the dexamethasone reference group. No evident treatment-associated systemic toxicity was detected under the experimental conditions. Integrated transcriptomic and Western blot analyses indicated suppression of NF-κB-associated pro-inflammatory signaling. These findings support CAAM-G as a promising corticosteroid-free topical platform for the treatment of AD, although further pharmacological and toxicological evaluation is required before clinical translation.