期刊
THERANOSTICS
卷 11, 期 7, 页码 3244-3261出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.54217
关键词
idiopathic pulmonary fibrosis (IPF); (myo)fibroblast; activation; apoptosis; siRNA; micelle
资金
- National Natural Science Foundation of China (NSFC) [81570059, 81830053, 81525014, 61821002, 82000069]
- Natural Science Foundation of Jiangsu Province of China [BK20151398, BK20200314]
- King Saud University, Riyadh, Saudi Arabia [RSP-2020/141]
The development of a dual siRNA-loaded micelle delivery system targeting (myo)fibroblasts shows promising potential in inhibiting the progression of pulmonary fibrosis by suppressing (myo)fibroblast activation and promoting apoptosis. The micelles effectively deliver siRNA targeting NOX4 and PTPN13, leading to significant antifibrotic effects without causing damage to major organs in murine models.
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-alpha (PDGFR alpha) 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.
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