Macrophage-targeted nanoparticles mediate synergistic photodynamic therapy and immunotherapy of tuberculosis

Na Tian; Huijuan Duan; Tingming Cao; Guangming Dai; Gang Sheng; Hongqian Chu; Zhaogang Sun

doi:10.1039/d2ra06334d

Macrophage-targeted nanoparticles mediate synergistic photodynamic therapy and immunotherapy of tuberculosis

RSC Adv. 2023 Jan 11;13(3):1727-1737. doi: 10.1039/d2ra06334d. eCollection 2023 Jan 6.

Authors

Na Tian^{1

2}, Huijuan Duan^{1

2}, Tingming Cao^{1

2}, Guangming Dai^{1

2}, Gang Sheng^{1

2}, Hongqian Chu^{1

2}, Zhaogang Sun^{1

2}

Affiliations

¹ Beijing Chest Hospital, Capital Medical University Beijing 101149 China sunzhaogang@bjxkyy.cn.
² Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Institute Beijing 101149 China.

Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that poses a serious global public health threat. Due to the high incidence of adverse reactions associated with conventional treatment regimens, there is an urgent need for better alternative therapies. CpG oligodeoxynucleotides (CpG ODNs) are synthetic oligodeoxyribonucleotide sequences. They can induce a Th1-type immune response by stimulating Toll-like receptors (TLRs) in mammalian immune cells, thus killing Mtb. However, due to the negative charge and easy degradation of CpG ODNs, it is necessary to deliver them into cells using nanomaterials. PCN-224 (hereinafter referred to as PCN), as a metal-organic framework based on zirconium ions and porphyrin ligands, not only has the advantage of high drug loading capacity, but also the porphyrin molecule in it is a type of photosensitizer, which allows these nanocomposites to play a role in photodynamic therapy (PDT) while delivering CpG ODNs. In addition, since Mtb mainly exists in macrophages, targeting anti-TB agents to macrophages is helpful to improve the anti-TB effect. Phosphatidylserine (PS) is a biological membrane phospholipid that is normally found on the inner side of cell membranes in, for example, plant and mammalian cells. When apoptosis occurs, PS can flip from the inner side of the cell membrane to the surface of the cell membrane, displaying a specific "eat-me" signal that can be recognized by specific receptors on macrophages. Therefore, we can use this macrophage-targeting property of PS to construct bio-inspired targeted drug delivery systems. In this study, we constructed PCN-CpG@PS nanocomposites. PCN-CpG@PS, combining PDT and immunotherapy, is designed to target macrophages at the site of a lesion and kill latent Mtb. We physically characterized the nanocomposites and validated their bactericidal ability in vitro and their ability to stimulate the immune system in vivo. The results demonstrated that the targeted nanocomposites have certain in vitro antituberculosis efficacy with good safety.