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Ahmet Umit Sabancı,1,* Perihan Erkan Alkan,2,* Cem Mujde,3,* Hivda Ulbeği Polat,4,* Cemre Ornek Erguzeloglu,5,* Atil Bisgin,3,6,* Cuneyt Ozakin,7,* Sehime G Temel5,8,9,* 1Bursa Çekirge State Hospital, Orthopedics and Traumatology Clinic, Bursa, Turkey; 2Bursa Uludağ University, Vocational School of Health Services, Medical Laboratory Technician Department, Bursa, Turkey; 3Çukurova University AGENTEM (Adana Genetic Diseases and Treatment Center), Adana, Turkey; 4TUBITAK, Marmara Research Center, Genetic Engineering and Biotechnology Institute, Gebze, Kocaeli, Turkey; 5Bursa Uludag University, Institute of Health Sciences, Department of Translational Medicine, Bursa, Turkey; 6Çukurova University, Faculty of Medicine, Department of Medical Genetics, Adana, Turkey; 7Bursa Uludağ University, Faculty of Medicine, Department of Infectious Diseases and Microbiology, Bursa, Turkey; 8Bursa Uludağ University, Faculty of Medicine, Department of Medical Genetics, Bursa, Turkey; 9Bursa Uludag University, Health Sciences Institute, Department of Translational Medicine, Bursa, Turkey*These authors contributed equally to this workCorrespondence: Cuneyt OzakinBursa Uludağ University, Faculty of Medicine, Department of Infectious Diseases and Microbiology, Bursa, TurkeyEmail ozakin@uludag.edu.trSehime G TemelBursa Uludağ University, Faculty of Medicine, Department of Medical Genetics, Bursa, TurkeyEmail sehime@uludag.edu.trPurpose: SARS-CoV-2-infected individuals may be asymptomatic, and therefore, the virus is highly contagious. We aimed to develop an agent to control viral replication in the upper respiratory tract and to prevent progression of the disease into the lower airways as well as inter-individual transmission. For this purpose, we investigated the antibacterial and antiviral activities of our novel nanobubble ozonated hyaluronic acid-decorated liposomal (NOHAL) solution, developed by using nanotechnology.Methods: The MIC levels of NOHAL solution were determined on blood agar cultures of Staphylococcus aureus (ATCC 6538), Streptococcuspneumoniae (ATCC 49619) and Escherichia coli (ATCC 25922). The in vitro anti-viral activity of NOHAL solution was studied using recombinant SARS-CoV-2 copies of the original virus, grown in Vero cells generated by reverse genetic technology. Human primary lung epithelial cells obtained by bronchoscopy or lung resection were used for cell viability tests using flow cytometry analysis. The cytotoxicity testing was performed using the BALB/c 3T3 (CCL-163) cell line. Skin, oral, nasal and ocular irritation tests were performed using New Zealand albino rabbits, Syrian hamsters, BALB c mice and New Zealand albino rabbits of both sexes.Results: Bacterial growth was prevented by NOHAL solution in a time-/dose-dependent manner. In vivo or in vitro experiments did not show any toxicity of NOHAL solution. No cytotoxicity was recorded on cell viability. No skin, oral, nasal or ocular toxicities were recorded. In addition, in a SARS-CoV-2 mouse infection model, NOHAL solution diminished the viral RNA levels effectively in nasopharyngeal and lung samples after its prophylactic intranasal application.Conclusion: NOHAL solution has the potential to reduce or prevent the spread of SARS-CoV-2 through the nose and/or oral cavity. The clinical efficacy of this solution needs to be tested in order to determine its efficacy in the early phase of COVID-19.Keywords: nanobubble, ozone, hyaluronic acid, liposome, anti-microbial, anti-viral