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Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis
Jingga Morry1, Worapol Ngamcherdtrakul1, Shenda Gu1
1Department of Biomedical Engineering, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR 97239, USA.
Abstract:
Fibrotic diseases such as scleroderma have been linked to increased oxidative stress and upregulation of pro-fibrotic genes. Recent work suggests a role of NADPH oxidase 4 (NOX4) and heat shock protein 47 (HSP47) in inducing excessive collagen synthesis, leading to fibrotic diseases. Herein, we elucidate the relationship between NOX4 and HSP47 in fibrogenesis and propose to modulate them altogether as a new strategy to treat fibrosis. We developed a nanoparticle platform consisting of polyethylenimine (PEI) and polyethylene glycol (PEG) coating on a 50-nm mesoporous silica nanoparticle (MSNP) core. The nanoparticles effectively delivered small interfering RNA (siRNA) targeting HSP47 (siHSP47) in an in vitro model of fibrosis based on TGF-β stimulated fibroblasts. The MSNP core also imparted an antioxidant property by scavenging reactive oxygen species (ROS) and subsequently reducing NOX4 levels in the in vitro fibrogenesis model. The nanoparticle was far superior to n-acetyl cysteine (NAC) at modulating pro-fibrotic markers. In vivo evaluation was performed in a bleomycin-induced scleroderma mouse model, which shares many similarities to human scleroderma disease. Intradermal administration of siHSP47-nanoparticles effectively reduced HSP47 protein expression in skin to normal level. In addition, the antioxidant MSNP also played a prominent role in reducing the pro-fibrotic markers, NOX4, alpha smooth muscle actin (α-SMA), and collagen type I (COL I), as well as skin thickness of the mice.
Insights
This study introduces a novel nanoparticle therapy that simultaneously targets heat shock protein 47 (HSP47) and reduces oxidative stress, effectively treating fibrotic diseases like scleroderma by modulating key pro-fibrotic markers.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Dermatology
Background:
- Fibrotic diseases, including scleroderma, are associated with elevated oxidative stress and pro-fibrotic gene expression.
- NADPH oxidase 4 (NOX4) and heat shock protein 47 (HSP47) are implicated in excessive collagen synthesis, driving fibrosis.
Purpose of the Study:
- To investigate the interplay between NOX4 and HSP47 in fibrogenesis.
- To develop and evaluate a nanoparticle-based strategy for simultaneous modulation of NOX4 and HSP47 to treat fibrosis.
Main Methods:
- Development of a mesoporous silica nanoparticle (MSNP) platform coated with polyethylenimine (PEI) and polyethylene glycol (PEG).
- In vitro delivery of small interfering RNA targeting HSP47 (siHSP47) to TGF-β stimulated fibroblasts.
- In vivo evaluation in a bleomycin-induced scleroderma mouse model.
Main Results:
- Nanoparticles effectively delivered siHSP47, reducing HSP47 protein expression in vitro and in vivo.
- The MSNP core demonstrated antioxidant properties, scavenging reactive oxygen species (ROS) and decreasing NOX4 levels.
- The nanoparticle therapy outperformed n-acetyl cysteine (NAC) in modulating pro-fibrotic markers and reduced skin thickness in the mouse model.
Conclusions:
- The developed nanoparticle platform offers a dual-action approach for treating fibrosis by targeting HSP47 and mitigating oxidative stress.
- This strategy effectively reduces key fibrotic markers, including NOX4, α-SMA, and collagen type I, presenting a promising therapeutic avenue for fibrotic conditions.
