iRGD conjugated nimbolide liposomes protect against endotoxin induced acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a deadly respiratory illness associated with refractory hypoxemia and pulmonary edema. The recent pandemic outbreak of COVID-19 is associated with severe pneumonia and inflammatory cytokine storm in the lungs. The anti-inflammatory phytomedicine nimbolide (NIM) may not be feasible for clinical translation due to poor pharmacokinetic properties and lack of suitable delivery systems. To overcome these barriers, we have developed nimbolide liposomes conjugated with iRGD peptide (iRGD-NIMLip) for targeting lung inflammation. It was observed that iRGD-NIMLip treatment significantly inhibited oxidative stress and cytokine storm compared to nimbolide free-drug (f-NIM), nimbolide liposomes (NIMLip), and exhibited superior activity compared to dexamethasone (DEX). iRGD-NIMLip abrogated the LPS induced p65 NF-κB, Akt, MAPK, Integrin β3 and β5, STAT3, and DNMT1 expression. Collectively, our results demonstrate that iRGD-NIMLip could be a promising novel drug delivery system to target severe pathological consequences observed in ARDS and COVID-19 associated cytokine storm. iRGD conjugated nimbolide liposomes (iRGD-NIMLip) were prepared by thin-film hydration method. Therapeutic potential of iRGD-NIMLip was tested in LPS induced acute respiratory distress syndrome (ARDS). iRGD peptide binds to integrins αv and α3/5 and further cleaves by protease and interacts with Neuropilin-1 (NRP-1) in lungs. Further liposomes enter into the cell by endocytic mechanism and inhibit the Toll like receptor-4 (TLR-4) mediated inflammatory signaling pathways. This novel drug delivery system inhibits the cytokine storm and oxidative stress by downregulating the STAT3 and DNMT-1 nuclear translocation. Thus, this novel formulation involves in ameliorating ARDS and might be useful in treating COVID-19 associated cytokine storm. [Display omitted] •iRGD-NIMLip selectively bind to the inflammatory sites and ameliorated the LPS induced ARDS by suppressing Integrins β3 and β5 expression.•Oropharyngeal administration of iRGD-NIMLip inhibited the LPS induced inflammatory mediated cells and lung edema compared to f-NIM, iRGDLip and NIMLip.•iRGD-NIMLip downregulated the p65 NF-κB signaling pathway and suppressed the COX-2 and iNOS mediated inflammation.•iRGD-NIMLip inhibited the LPS induced oxidative and nitrosative stress.•iRGD-NIMLip downregulated the STAT3 and DNMT1 expression and suppressed the cytokine storm and might be beneficial in COVID-19 associ