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

Theranostics. 2021 Jan 9;11(7):3244-3261. doi: 10.7150/thno.54217. eCollection 2021.


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: (myo)fibroblast; activation; apoptosis; idiopathic pulmonary fibrosis (IPF); micelle; siRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / administration & dosage
  • Drug Delivery Systems / methods*
  • Gene Expression
  • Humans
  • Idiopathic Pulmonary Fibrosis / chemically induced
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Idiopathic Pulmonary Fibrosis / therapy*
  • Immunoglobulin Fab Fragments / genetics
  • Immunoglobulin Fab Fragments / metabolism
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Micelles
  • Molecular Targeted Therapy / methods*
  • Myofibroblasts / metabolism*
  • Myofibroblasts / pathology
  • NADPH Oxidase 4 / antagonists & inhibitors
  • NADPH Oxidase 4 / genetics*
  • NADPH Oxidase 4 / metabolism
  • Primary Cell Culture
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Treatment Outcome


  • Immunoglobulin Fab Fragments
  • Micelles
  • RNA, Small Interfering
  • Bleomycin
  • NADPH Oxidase 4
  • Nox4 protein, mouse
  • Receptor, Platelet-Derived Growth Factor alpha
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13
  • Ptpn13 protein, mouse