Xiaoying Jin,1,2,* Jiajun Wang,1,2,* Yongdui Ruan,1,* Jiaxiang Li,1,2 Xinen Kong,1,2 Jiaojiao Xia,3 Jiayi Yang,1,2 Qiao Zhang,3 Juan Liu,1,2 Jiang Pi1,2 

1Research Center of Nanotechnology and Application Engineering, School of Medical Technology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, People’s Republic of China; 2Dongguan Key Laboratory for Pathogenesis and Experimental Diagnosis of Infectious Diseases, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, 650500, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jiang Pi, Email jiangpi@gdmu.edu.cn Qiao Zhang, Email zhangqiao200824@126.com

Abstract: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the most prevalent infectious diseases worldwide. Nitric oxide (NO) is produced by the reaction of arginine and oxygen catalyzed by nitric oxide synthase (NOS) in mammals. Several studies have highlighted the potential therapeutic use of NO for the treatment of various diseases, including infectious diseases. NO plays a direct bactericidal role by damaging the bacterial DNA, proteins, and enzymes. Additionally, it plays a role in modulating immune cell function, contributing to their anti-tuberculosis (anti-TB) effects by regulating macrophage activity. NO has also been shown to eliminate bacterial biofilms, thereby increasing drug sensitivity of drug-resistant bacteria. Therefore, combining NO with antibiotics may be a strategy for treating drug-resistant tuberculosis (DR-TB). However, owing to the limitations of NO, including their short half-life, instability, and cytotoxicity, exogenous supplementation with NO donors has emerged as a promising alternative therapy. Rapid advancements in nanotechnology have led to the development of nanoparticles (NPs) as drug delivery platforms, at the same time, using strategies such as introducing selective organ targeting (SORT) molecules into nanocarrier systems or preparing nanodrugs in inhalable or dry powder inhalation forms can increase the accumulation of nanodrugs in the lungs. Combined with host-directed therapy strategies, this can improve the therapeutic effect on tuberculosis and shorten the treatment time. This review summarizes the biological activities of NO and introduces their applications in the treatment of several major infectious diseases, followed by a systemic analysis of the role and mechanism of action of NO in TB treatment. Moreover, nanotechnology-assisted NO therapeutics are also summarized to explore the potential for more effective Mtb killing based on the advantages of targeted NO release at the infected site and host cells, thus benefiting the development of more effective therapeutics against TB and drug-resistant TB.

Keywords: nitric oxide, nitric oxide donors, nanotechnology, tuberculosis