Citation: Jokar, S.; Marques, I.A.; Khazaei, S.; Martins-Marques, T.; Girao, H.; Laranjo, M.; Botelho, M.F. The Footprint of Exosomes in the Radiation-Induced Bystander Effects. Bioengineering 2022, 9, 243. https://doi.org/10.3390/ bioengineering9060243 Academic Editor: Zhen Cheng Received: 30 March 2022 Accepted: 26 May 2022 Published: 31 May 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 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/). bioengineering Review The Footprint of Exosomes in the Radiation-Induced Bystander Effects Safura Jokar 1,2,3,4 , Inês A. Marques 2,3,4,5,6 , Saeedeh Khazaei 7 , Tania Martins-Marques 3,4,8 , Henrique Girao 3,4,8 , Mafalda Laranjo 2,3,4,5,8 and Maria Filomena Botelho 2,3,4,5,8, * 1 Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran P94V+927, Iran; jokar.safura@gmail.com 2 Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; ines.marques@student.uc.pt (I.A.M.); mafaldalaranjo@gmail.com (M.L.) 3 Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; tania.m.marques@fmed.uc.pt (T.M.-M.); hmgirao@fmed.uc.pt (H.G.) 4 Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal 5 Centre of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal 6 Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal 7 Department of Pharmaceutical Biomaterials, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran P94V+927, Iran; saeede.khazaei@gmail.com 8 Clinical and Academic Centre of Coimbra (CACC), 3004-561 Coimbra, Portugal * Correspondence: mfbotelho@fmed.uc.pt Abstract: Radiation therapy is widely used as the primary treatment option for several cancer types. However, radiation therapy is a nonspecific method and associated with significant challenges such as radioresistance and non-targeted effects. The radiation-induced non-targeted effects on nonirradiated cells nearby are known as bystander effects, while effects far from the ionising radiation-exposed cells are known as abscopal effects. These effects are presented as a consequence of intercellular communi- cations. Therefore, a better understanding of the involved intercellular signals may bring promising new strategies for radiation risk assessment and potential targets for developing novel radiotherapy strategies. Recent studies indicate that radiation-derived extracellular vesicles, particularly exosomes, play a vital role in intercellular communications and may result in radioresistance and non-targeted effects. This review describes exosome biology, intercellular interactions, and response to different environmental stressors and diseases, and focuses on their role as functional mediators in inducing radiation-induced bystander effect (RIBE). Keywords: radiation therapy; exosome; bystander effects; radioresistance; cancer 1. Introduction Cancer is a major health issue in the world, accounting for about 10.0 million deaths worldwide in 2020, as estimated by International Agency for Research on Cancer (IARC). Due to the rapid growth and aging of the population and the increasing prevalence of high-risk factors, it is expected that the number of cancer-affected patients will reach more than 28.4 million cases worldwide by 2040 [1,2]. Radiation therapy (RT) is one of the comprehensive and highly cost-effective modalities for cancer patients, accounting for only 5% of the total cost of cancer therapy [3,4]. Electromagnetic radiations (X-rays or gamma rays) are types of radiation used in RT, with X-rays being generated through linear accelerators (LINAC), while gamma rays are emitted during radioactive nucleus decay (cobalt-60 at gamma-knife). These radiations are considered low linear energy transfer (LET) [3]. The X-rays from LINACs are widely applied in more than 50% of cancer patients for curative and palliative purposes, separately or combined with other Bioengineering 2022, 9, 243. https://doi.org/10.3390/bioengineering9060243 https://www.mdpi.com/journal/bioengineering