Title : Delivery of NRF2 via mRNA-LNP platform to inhibit the progression of pulmonary fibrosis
Abstract:
A key pathological driver is the excessive accumulation of Reactive Oxygen Species (ROS) within the alveolar microenvironment. This oxidative stress triggers the differentiation of fibroblasts into myofibroblasts, resulting in aberrant Extracellular Matrix (ECM) deposition and the destruction of normal lung architecture. Although nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcription factor that maintains redox homeostasis by regulating the Antioxidant Response Element (ARE) pathway, its expression and activity decline significantly with aging and clinical progression of IPF. This NRF2 deficiency exacerbates oxidative vulnerability, creating a vicious cycle that accelerates fibrotic pathology. To address these limitations, a Lipid Nanoparticle (LNP)-based mRNA platform was utilized in this study to restore NRF2 levels and bolster the endogenous pulmonary antioxidant defense system. The use of an LNP-mRNA system allows for the rapid and transient expression of NRF2, bypassing the risks associated with viral vectors or genomic integration. To validate this approach, NRF2 mRNA was delivered to senescence-induced fibroblasts in vitro. ROS levels were significantly reduced following the treatment, and the expression of key molecular markers, including p21 and NAD(P)H quinone dehydrogenase 1 (NQO1), was restored to homeostatic levels, effectively mitigating cellular senescence. In addition, the in vivo efficacy and safety of the NRF2 mRNA-LNP system are to be evaluated using a bleomycin-induced pulmonary fibrosis mouse model. Histopathological analysis and lung function tests will be conducted to confirm the suppression of collagen deposition and fibrotic progression. These findings suggest that mRNA-mediated NRF2 restoration demonstrates a potent and versatile therapeutic strategy for IPF and other age-related oxidative diseases, potentially offering a superior alternative to conventional pharmacological NRF2 activators.
