Suppressing Sart1 to modulate macrophage polarization by siRNA-loaded liposomes: a promising therapeutic strategy for pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and diffuse form of interstitial lung disease of unknown etiology with a fatal outcome. Although various strategies for IPF have been developed over the last few decades, no significant positive impact on the prognosis of IPF has been observed. According to the current paradigm, macrophages have been recognized to play a significant role in IPF pathogenesis. Here, we report a potential nanomedicine-based gene therapy for IPF based on regulate macrophage polarization. Method: C57BL/6 mice were obtained and used to establish a bleomycin (BLM)-induced pulmonary fibrosis animal model, and Sart1 siRNA-loaded liposomes were designed for in vivo experiment. The experimental animals were administered BLM intratracheally on day 0 and treated with Sart1 siRNA on days 14 and 17. In the in vitro experiment, we further examined the function of Sart1 in macrophages. Results: Our data indicated that the liposomes could passively target the fibrotic area in the lung and efficiently accumulate in macrophages. The suppression of Sart1 by siRNA-loaded liposomes significantly protected mice against BLM-induced lung injury and fibrosis, which was attributed to attenuated M2 macrophage infiltration in the lung. Conclusion: Our study provides a valuable reference for modulating macrophage polarization and a promising strategy for the treatment of pulmonary fibrosis in clinical settings.

Targeted Inhibition of FTO Demethylase Protects Mice Against LPS-Induced Septic Shock by Suppressing NLRP3 Inflammasome

“…DiI-loaded liposomes were prepared as previously described (28). The mice were intraperitoneally injected with liposomes and anesthetized at different time points.…”

Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition

“…Although numerous clinical trials have been carried out to characterize viable drugs for IPF, unfortunately, no effective therapeutic approach was currently available to cure or even halt the progression of IPF 31 . Previous studies 30 , 36 , including our 15 , have illustrated that liposomes loading with siRNA are established as drug carriers for airway injection owing to their safety and effectiveness to provide controlled drug release in the lung. Inspiringly, patisiran, the first siRNA drug based on liposomes, was approved by the FDA in 2018, moving the concept to clinical settings 37 .…”

“…Previous studies 13 , 14 , including ours 15 , demonstrated that cationic liposomes are promising strategies for the siRNA-based therapy of various disease. Especially for pulmonary fibrosis, we have verified that liposomes administrated by intratracheal injection, equivalent to clinical atomization treatment, preferred to accumulate in the fibrotic lesion, in which consists of abundant fibroblasts and/or myofibroblasts.…”

“…And then, the prepared liposomes were intratracheal injected to the C57/B6 mice. The mice were then anesthetized and imaged at different time points (0 h, 2 h, 8 h, 3 d, 6 d) by an in vivo imaging system (IVIS Lumina XR, SI Imaging, AZ, USA) (excitation: 745 nm, emission: 830 nm) as previous reported 15 . After 6 d, the mice were sacrificed, and the organs and serum were harvested for ex vivo fluorescence imaging and biochemical detection, respectively.…”

Beyond “Big Eaters”: The Versatile Role of Alveolar Macrophages in Health and Disease

“…The authors report a dose-dependent decrease of CD206, TGF-β and α-SMA expression in bleomycin-induced fibrosis. Another approach reported liposome-mediated delivery of siRNA against spliceosome associated factor 1 ( Sart1 ), which was shown to be involved in oxygen-independent HIF-1α degradation and macrophage M2 polarization, to attenuate M2 macrophage polarization in fibrotic lungs [ 85 ]. Additionally, a novel phosphodiesterase 4 (PDE4) inhibitor has been tested for antifibrotic effects in a bleomycin-induced mouse model [ 86 ].…”