Lung-targeting lipid nanoparticle-mediated sparstolonin B delivery improves acute lung injury.

Acute respiratory distress syndrome (ARDS), a severe manifestation of acute lung injury (ALI), is characterized by high morbidity and mortality, with limited therapeutic options. Sparstolonin B (SsnB), a selective antagonist of Toll-like receptors (TLR)-2 and TLR-4 with significant anti-inflammatory activity, has been studied in various diseases. However, its potential for targeted delivery to lung tissues in the treatment of ARDS/ALI remains an underexplored area warranting further investigation. Here, we report the development of a lung-targeting sulfonium lipid nanoparticle (sLNP)-mediated SsnB delivery system in a murine model of lipopolysaccharide (LPS)-induced ALI. Comprehensive analyses of serum, bronchoalveolar lavage fluid (BALF), and lung tissues post-injury revealed that SsnB-loaded sLNP (SsnB/sLNP) significantly mitigated lung injury. This was evidenced by improved lung histology, reduced macrophage counts and neutrophil infiltration in BALF, and decreased levels of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, in both BALF and serum. Mechanistic studies further demonstrated that the therapeutic effects of SsnB were mediated through the inhibition of the NF-κB signaling pathway. These findings highlight the potential of lung-targeting sLNP-mediated SsnB delivery as a promising therapeutic strategy for ALI and ARDS.