Ultrasound targeted fatty acid nitroalkene-containing lipid nanoparticles attenuate inflammation and reverse...

Myocardial ischemia-reperfusion injury (MIRI) induces oxidative stress and inflammatory signaling that drive fibroblast activation, myocardial fibrosis, and progressive cardiac dysfunction, for which effective targeted therapies remain limited. The electrophilic fatty acid nitroalkene 10-nitro-octadec-9-enoic acid (NO₂-FA) exhibits anti-inflammatory and antifibrotic properties but pharmacological actions have been limited by extents of myocardial delivery. Ultrasound-targeted cavitation (UTC) using lipid-shelled gas-filled nanoparticles (LNPs) enables spatially controlled drug release and represents a promising theranostic strategy.

NO₂-FA were incorporated in LNPs and delivered focally to the myocardium using UTC. Therapeutic efficacy was evaluated in rodent models of MIRI and myocardial fibrosis. In the MIRI model, animals received UTC + NO₂-FA LNPs, intravenous NO₂-FA, or sham treatment. Cardiac structure, function, and molecular remodeling were assessed using echocardiography, histological staining, polymerase chain reaction, and enzyme-linked immunosorbent assay. In the myocardial fibrosis model, additional analyses included immunohistochemistry and cardiovascular magnetic resonance imaging.

UTC-mediated delivery of NO₂-FA LNPs significantly reduced myocardial fibrosis compared with intravenous NO₂-FA (p = 0.03) and sham treatment (p = 0.001), as demonstrated by histological quantification and reduced late gadolinium enhancement. Targeted NO₂-FA delivery also improved cardiac output and favorably modulated molecular markers associated with fibrosis and inflammation. Across both experimental models, UTC-facilitated NO₂-FA delivery consistently demonstrated superior therapeutic efficacy relative to non-targeted administration.

Spatially targeted delivery of NO₂-FA using ultrasound-mediated cavitation enhances cardioprotective and antifibrotic effects in experimental models of MIRI and myocardial fibrosis. This platform integrates targeted therapy with imaging-based assessment and supports further development of UTC-enabled theranostic approaches for ischemic heart disease.