Mesoporous nanoparticles delivering miRNA-125b inhibitor attenuates cigarette smoke-induced inflammation and senescence in lung epithelial cells

Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung condition driven by chronic inflammation, cellular senescence, and impaired tissue repair that is often exacerbated by exposure to primary or even secondary cigarette smoke. Among prominent pathological hallmarks, microRNAs, especially microRNA-125b (miR-125b) has emerged as a key regulator in COPD pathogenesis, being consistently upregulated. In this study, we investigated the therapeutic potential of miR-125b inhibitor encapsulated in mesoporous silica nanoparticles (MPS), an advanced nanocarrier system well-known for its high surface area, tunable pore size, excellent biocompatibility enabling efficient delivery and protection of fragile nucleic acid-based therapeutics such as miRNA inhibitors. An in vitro cigarette smoke extract (CSE)-induced model in the bronchial epithelial cells (BCiNS1.1) was employed. The nanoparticle-delivered miR-125b inhibitor demonstrated significant anti-inflammatory and anti-senescence activity compared to the scramble control. Treatment reduced CSE-induced upregulation of IL-1β and FGF-basic while restoring the CSE-triggered suppression of CXCL10, VEGF, RANTES etc. Anti-senescence effects were confirmed through decreased p21 expression and reduced X-gal staining. Transcriptomic analysis of COPD lung tissue (GSE38974) revealed upregulation of miR-125b with concurrent suppression of several protective targets, including SIRT1, VDR, CXCL10, and FGF1. These clinical expression patterns align with our in vitro findings in cigarette smoke extract-stimulated bronchial epithelial cells, where miR-125b inhibition reduced senescence and restored inflammatory mediators. Together, these data support miR-125b as a clinically relevant regulator of COPD-associated inflammatory and senescent pathways. While these findings underscore the therapeutic promise of miR-125b inhibition, future studies employing in vivo models, advanced airway tissue systems and optimised pulmonary strategies such as inhalable or nasal MPS formulation approaches are warranted to validate the biodistribution, pharmacokinetic and pharmacodynamic effects and translate these outcomes. This nanocarrier-based approach presents a compelling strategy for targeted molecular intervention in chronic respiratory diseases like COPD.