Citation: Di Raimo, R.; Mizzoni, D.; Spada, M.; Dolo, V.; Fais, S.; Logozzi, M. Oral Treatment with Plant-Derived Exosomes Restores Redox Balance in H 2 O 2 -Treated Mice. Antioxidants 2023, 12, 1169. https:// doi.org/10.3390/antiox12061169 Academic Editor: Roberta Fusco Received: 26 April 2023 Revised: 22 May 2023 Accepted: 25 May 2023 Published: 29 May 2023 Copyright: © 2023 by the authors. 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/licenses/by/ 4.0/). antioxidants Article Oral Treatment with Plant-Derived Exosomes Restores Redox Balance in H 2 O 2 -Treated Mice Rossella Di Raimo 1,2,† , Davide Mizzoni 1,2,† , Massimo Spada 1 , Vincenza Dolo 3 , Stefano Fais 1, * and Mariantonia Logozzi 1, * 1 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; rossella.diraimo@iss.it or rossella@exolabitalia.com (R.D.R.); davide.mizzoni@iss.it or davide@exolabitalia.com (D.M.); massimo.spada@iss.it (M.S.) 2 ExoLab Italia, Tecnopolo d’Abruzzo, 67100 L’Aquila, Italy 3 Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; vincenza.dolo@univaq.it * Correspondence: stefano.fais@iss.it (S.F.); mariantonia.logozzi@iss.it (M.L.); Tel.: +39-0649903195 (M.L.); Fax: +39-0649902436 (M.L.) † These authors contributed equally to this work. Abstract: Plant-derived exosomes (PDEs) are receiving much attention as a natural source of antioxi- dants. Previous research has shown that PDEs contain a series of bioactives and that their content varies depending on the fruit or vegetable source. It has also been shown that fruits and vegetables derived from organic agriculture produce more exosomes, are safer, free of toxic substances, and contain more bioactives. The aim of this study was to investigate the ability of orally administered mixes of PDE (Exocomplex ® ) to restore the physiological conditions of mice treated for two weeks with hydrogen peroxide (H 2 O 2 ), compared with mice left untreated after the period of H 2 O 2 admin- istration and mice that received only water during the experimental period. The results showed that Exocomplex ® had a high antioxidant capacity and contained a series of bioactives, including Catalase, Glutathione (GSH), Superoxide Dismutase (SOD), Ascorbic Acid, Melatonin, Phenolic compounds, and ATP. The oral administration of Exocomplex ® to the H 2 O 2 -treated mice re-established redox balance with reduced serum levels of both reactive oxygen species (ROS) and malondialdehyde (MDA), but also a general recovery of the homeostatic condition at the organ level, supporting the future use of PDE for health care. Keywords: plant-derived exosomes; antioxidants; anti-aging; anti-stress; natural bioactives; health; organic agriculture; plants 1. Introduction Reactive oxygen species (ROS) are mainly produced in mitochondria and are involved in various physiological activities, acting as both messengers of cell signaling and regulator of many cellular functions, including gene expression, proliferation, differentiation, and stress response [1]. The redox imbalance due to the absolute increase in ROS formation contributes to marked alteration of physiological functions [2], also leading to disease development [1,3,4]. These apparently contradictory effects are due to the imbalance be- tween the oxidative and the reducing processes, a condition known as oxidative stress, inevitably leading to cell and tissue damage. In fact, oxidative stress is involved in the activation of a variety of transcription factors, in turn contributing to the activation of inflammatory pathways related to altered gene expression and often to the process of telomere shortening [5]. As a consequence, inflammation triggered by oxidative stress represents a major cause of many chronic pathologic conditions, including neurodegen- erative diseases and cancers [1,6]. The role of oxidative stress in the aging process [7], induced by the progressive accumulation of ROS into the cells of the various organs and Antioxidants 2023, 12, 1169. https://doi.org/10.3390/antiox12061169 https://www.mdpi.com/journal/antioxidants