Smart-NADES Licorice Extract as a Pharmacologically Active Phytocomplex: From Antioxidant Synergism to Anti-Inflammatory Hydrogel Efficacy

Background/Objectives: The pharmacological management of inflammation remains a clinical challenge, driving the demand for advanced topical formulations. This study utilizes a “smart-NADES” (natural deep eutectic solvent) paradigm to develop an innovative anti-inflammatory topical system. The aim was to evaluate the integrated antioxidant potential, alongside the in vitro and in vivo anti-inflammatory activities, of a novel smart-NADES licorice root extract and its hydrogel formulation. Methods: A NADES system composed of D-sorbitol and L-lactic acid (3:1) was employed for licorice root extraction. The antioxidant capacity was assessed using three independent assays and integrated via the Relative Antioxidant Capacity Index (RACI), while phytochemical interactions were quantified using the Chou–Talalai Combination Index (CI). In vitro anti-inflammatory activity was evaluated via protein stabilization capacity, and in vivo efficacy was validated using a formalin-induced paw edema model in mice. Results: The NADES extract contained glycyrrhizic acid levels of 6.3 ± 0.3 mg/g and showed strong antioxidant synergism in the DPPH assay (CI = 0.49 ± 0.07). The extract exhibited potent total antioxidant capacity (IC50 = 11.9 ± 0.6 μg/mL) with a superior RACI score (1.23). In vitro protein stabilization (IC50 = 63 ± 5 μg/mL) was comparable to diclofenac sodium. The 5% hydrogel numerically surpassed the commercial 2% diclofenac Emulgel (67.5% vs. 32.9% inhibition, respectively) at 24 h, although the direct pairwise comparison did not reach statistical significance (p = 0.186). Conclusions: The developed smart-NADES licorice hydrogel represents an effective, green formulation with pronounced topical anti-inflammatory properties, establishing a robust pharmacological rationale for advanced topical drug delivery.