Abstract Background Acute respiratory distress syndrome(ARDS) is characterized by severe pulmonaryinflammation and epithelial injury, with high mobility groupbox 1 (HMGB1) being a keypro-inflammatory mediator. MicroRNA-1179 (miR-1179) binds tothe 3′UTR of HMGB1 mRNAand suppresses its expression, but efficient andorgan-specific delivery remains a major hurdle. Methods Serum samples from ARDS patients and healthycontrols were analyzed for HMGB1and miR-1179 expression and correlated with clinicalseverity and imaging scores. We thenengineered peptide-displaying exosomes by decorating theirsurface with a peptide candidate forlung epithelial targeting and loading them with miR-1179(ExoFITC-miR-1179). The modifiedexosomes were characterized and administered via mask-basednebulization in a murineLPS-induced ARDS model, simulating a noninvasive andclinically translatable delivery route.Lung-targeting and biodistribution were tracked using invivo imaging, and therapeutic efficacywas evaluated through histological, molecular, andimmunological analyses. Results ARDS patients exhibited elevated HMGB1levels and reduced miR-1179 expression,with inverse correlations to disease severity andradiographic lung injury. In mice,ExoFITC-miR-1179 effectively accumulated in lung epithelialtissue following nebulized inhalationand demonstrated enhanced uptake by alveolar epithelialcells. Treatment significantlydownregulated HMGB1 expression and inhibited NF-κB pathwayactivation. Correspondingly,levels of key inflammatory cytokines (TNF-α, IL-6, IL-1β)were markedly reduced.Histopathology confirmed alleviation of alveolar damage,reduced inflammatory infiltration, andimproved lung architecture. In contrast, unmodified exosomesor free miR-1179 producedminimal effects. Conclusion This study provides preclinicalproof-of-concept evidence that exosome-mediateddelivery of miR-1179 can suppress HMGB1-driven inflammationin ARDS. By integrating alung-targeting peptide with nebulized administration, ourapproach provides a noninvasive,organ-specific proof-of-concept platform for therapeuticmiRNA delivery with potential for futuretranslation in inflammatory lung disease. This abstract is funded by: the Nanshan Science and Technology Foundation (Grant No. ZNSXS-20220080); the Independent Project of the State Key Laboratory of Respiratory Diseases (Grant No. SKLRD-Z-202305); the GMU Young Investigator Supporting Program (Grant No. Plan on Enhancing Scientific Research in GMU-2025SRP013); and the Guangdong Association for Science and Technology Program (Grant No. SKXRC2025113). Shanghai Municipal Science and Technology Major Project(ZD2021CY001), Li Shaoqiang received funding from the Guangdong Provincial Special Support Program for Outstanding Young Talents 2024, The Construction of Multi-Disciplinary Treatment System for Severe Pneumonia(W2020-013).
M Xue (Fri,) studied this question.