Introduction: ARDS is a severe condition with high mortality, particularly during viral outbreaks. Acute lung injury disrupts surfactant function, leading to alveolar collapse and hypoxemia. Exogenous surfactant therapies have limited efficacy in adults. Innovative strategies to preserve surfactant activity would significantly reduce the burden of injury. Aim: This study explores NM-002, a mesenchymal stem cell-responsive microRNA (miR) formulated in lipid nanoparticles (LNPs), to restore surfactant function in viral-induced ARDS by upregulating surfactant proteins C (SPC) and D (SPD). Methods: In a time-series analysis, we analyzed surfactant protein expression in H1N1-infected NM-002-miR-knockout (KO) and wild-type (WT) mice. Transcriptomic screening identified gene targets, with luciferase assays confirming the binding to the 3?UTR of targets. Surfactant functionality was assessed using bronchoalveolar lavage fluid (BALf) in a constrained sessile drop surfactometer (CDS) to measure surface tension reduction. Results: The KO mice showed significantly higher SPC levels, improved lung compliance, and reduced alveolar damage compared to WT. NM-002 treatment in ARDS models resulted in robust upregulation of SPC and SPD, with increased protein expression. Enhanced lamellar body integrity in alveolar type II cells was observed through electron microscopy. CDS analysis demonstrated improved surface tension reduction and stability in NM-002-treated mice. Conclusion: NM-002 offers a promising miR-based LNP therapy for ARDS by selectively enhancing surfactant proteins and restoring lung mechanics, addressing the limitations of conventional surfactant treatments in adult ARDS.