Biomedicines 2022, 10, 1039. https://doi.org/10.3390/biomedicines10051039 www.mdpi.com/journal/biomedicines Article Ammonium Glycyrrhizinate and Bergamot Essential Oil Co-Loaded Ultradeformable Nanocarriers: An Effective Natural Nanomedicine for In Vivo Anti-Inflammatory Topical Therapies Maria Chiara Cristiano 1,† , Nicola d’Avanzo 2,† , Antonia Mancuso 1 , Martine Tarsitano 3 , Antonella Barone 1 , Daniele Torella 1 , Donatella Paolino 1, * and Massimo Fresta 3 1 Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro Campus Universitario-Germaneto, Viale Europa, 88100 Catanzaro, Italy; mchiara.cristiano@unicz.it (M.C.C.); antonia.mancuso@unicz.it (A.M.); barone@unicz.it (A.B.); dtorella@unicz.it (D.T.) 2 Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini n.31, 66100 Chieti, Italy; nicola.davanzo@unich.it 3 Department of Health Science, University “Magna Græcia” of Catanzaro Campus Universitario-Germaneto, Viale Europa, 88100 Catanzaro, Italy; martine.tarsitano@studenti.unicz.it (M.T.); fresta@unicz.it (M.F.) * Correspondence: paolino@unicz.it; Tel.: +39-0961-3694-211 † These authors contributed equally to this work. Abstract: Bergamot essential oil (BEO) and Ammonium glycyrrhizinate (AG), naturally derived compounds, have remarkable anti-inflammatory properties, thus making them suitable candidates for the treatment of skin disorders. Despite this, their inadequate physicochemical properties strongly compromise their topical application. Ultradeformable nanocarriers containing both BEO and AG were used to allow their passage through the skin, thus maximizing their therapeutic activity. Physicochemical characterization studies were performed using Zetasizer Nano ZS and Turbiscan Lab ® . The dialysis method was used to investigate the release profile of the active compounds. In vivo studies were performed on human healthy volunteers through the X-Rite spectrophotometer. The nanosystems showed suitable features for topical cutaneous administration in terms of mean size, surface charge, size distribution, and long-term stability/storability. The co-delivery of BEO and AG in the deformable systems improved both the release profile kinetic of ammonium glycyrrhizinate and deformability properties of the resulting nanosystems. The topical cutaneous administration on human volunteers confirmed the efficacy of the nanosystems. In detail, BEO and AG-co-loaded ultradeformable vesicles showed a superior activity compared to that recorded from the ones containing AG as a single agent. These results are promising and strongly encourage a potential topical application of AG/BEO co-loaded nanocarriers for anti-inflammatory therapies. Keywords: ammonium glycyrrhizinate; bergamot essential oil; ultradeformable nanocarriers; multi-drug carriers; in vivo anti-inflammatory activity 1. Introduction Essential oils and phytotherapic molecules overall caught the attention since ancient times [1–4], and in recent decades several research groups tried to exploit their benefits, improving their poor physicochemical properties using nanotechnologies [5–7]. In fact, nanotechnologies and drug delivery systems have already obtained plenty of experience behind them, thus allowing optimization of common therapies; and although few nanomedicines are actually on market, the advantages in their use remain undoubted [8]. Citrus bergamia, originally from the extreme south of the Italian peninsula, is known as Bergamot, and its essential oil extracted (BEO), is world-famous for its several Citation: Cristiano, M.C.; d’Avanzo, N.; Mancuso, A.; Tarsitano, M.; Barone, A.; Torella, D.; Paolino, D.; Fresta, M. Ammonium Glycyrrhizinate and Bergamot Essential Oil Co-Loaded Ultradeformable Nanocarriers: An Effective Natural Nanomedicine for In Vivo Anti-Inflammatory Topical Therapies. Biomedicines 2022, 10, 1039. https://doi.org/10.3390/ biomedicines10051039 Academic Editors: Elisabete M. S. Castanheira and Sérgio R. S. Veloso Received: 14 April 2022 Accepted: 28 April 2022 Published: 30 April 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/license s/by/4.0/).