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Theranostics 2021; 11(7):3244-3261. doi:10.7150/thno.54217 This issue Cite

Research Paper

Co-delivery of siPTPN13 and siNOX4 via (myo)fibroblast-targeting polymeric micelles for idiopathic pulmonary fibrosis therapy

Jiwei Hou^1,2#, Qijian Ji^3,4#, Jie Ji^1,2, Shenghong Ju^5✉, Chun Xu⁶, Xueqing Yong⁷, Xiaoxuan Xu⁵, Mohd. Muddassir⁸, Xiang Chen^1,2, Jinbing Xie^5✉, Xiaodong Han^1,2✉

1. Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, China.
2. Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
3. Department of Critical Care Medicine, Xuyi People's Hospital, 28 Hongwu Road, Xuyi, 211700, Jiangsu, China.
4. Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China.
5. Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing 210009, China.
6. Department of Pathology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210009, China.
7. Department of Nuclear Science & Technology, Nanjing University of Aeronautics and Astronautics, Nanjing, 211106, China.
8. Department of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
#These authors contributed equally to this work.

✉ Corresponding authors: Sheng-hong Ju (jsh0836com), Jinbing Xie (xiejbedu.cn) or Xiaodong Han (hanxdedu.cn).

Abstract

Rationale: (Myo)fibroblasts are the ultimate effector cells responsible for the production of collagen within alveolar structures, a core phenomenon in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Although (myo)fibroblast-targeted therapy holds great promise for suppressing the progression of IPF, its development is hindered by the limited drug delivery efficacy to (myo)fibroblasts and the vicious circle of (myo)fibroblast activation and evasion of apoptosis.

Methods: Here, a dual small interfering RNA (siRNA)-loaded delivery system of polymeric micelles is developed to suppress the development of pulmonary fibrosis via a two-arm mechanism. The micelles are endowed with (myo)fibroblast-targeting ability by modifying the Fab' fragment of the anti-platelet-derived growth factor receptor-α (PDGFRα) antibody onto their surface. Two different sequences of siRNA targeting protein tyrosine phosphatase-N13 (PTPN13, a promoter of the resistance of (myo)fibroblasts to Fas-induced apoptosis) and NADPH oxidase-4 (NOX4, a key regulator for (myo)fibroblast differentiation and activation) are loaded into micelles to inhibit the formation of fibroblastic foci.

Results: We demonstrate that Fab'-conjugated dual siRNA-micelles exhibit higher affinity to (myo)fibroblasts in fibrotic lung tissue. This Fab'-conjugated dual siRNA-micelle can achieve remarkable antifibrotic effects on the formation of fibroblastic foci by, on the one hand, suppressing (myo)fibroblast activation via siRNA-induced knockdown of NOX4 and, on the other hand, sensitizing (myo)fibroblasts to Fas-induced apoptosis by siRNA-mediated PTPN13 silencing. In addition, this (myo)fibroblast-targeting siRNA-loaded micelle did not induce significant damage to major organs, and no histopathological abnormities were observed in murine models.

Conclusion: The (myo)fibroblast-targeting dual siRNA-loaded micelles offer a potential strategy with promising prospects in molecular-targeted fibrosis therapy.

Keywords: idiopathic pulmonary fibrosis (IPF), (myo)fibroblast, activation, apoptosis, siRNA, micelle

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