Sepsis is an acute inflammatory syndrome in response to
infection. In some cases, excessive
inflammation from
sepsis results in endothelial dysfunction and subsequent increased vascular permeability leading to organ failure. We previously showed that treatment with endothelial progenitor cells, which highly express microRNA-126 (miR-126), improved survival in mice subjected to cecal
ligation and
puncture (CLP)
sepsis.
miRNAs are important regulators of gene expression and cell function, play a major role in endothelial homeostasis, and may represent an emerging therapeutic modality. However, delivery of
miRNAs to cells in vitro and in vivo is challenging due to rapid degradation by ubiquitous RNases. Herein, we developed a nanoparticle delivery system separately combining deacetylated
poly-N-acetyl glucosamine (DEAC-pGlcNAc)
polymers with miRNA-126-3p and miRNA-126-5p and testing these combinations in vitro and in vivo. Our results demonstrate that DEAC-pGlcNAc
polymers have an appropriate size and zeta potential for cellular uptake and when complexed, DEAC-pGlcNAc protects
miRNA from
RNase A degradation. Further, DEAC-pGlcNAc efficiently encapsulates
miRNAs as evidenced by preventing their migration in an
agarose gel. The DEAC-pGlcNAc-
miRNA complexes were taken up by multiple cell types and the delivered
miRNAs had
biological effects on their targets in vitro including pERK and DLK-1. In addition, we found that delivery of DEAC-pGlcNAc alone or DEAC-pGlcNAc:
miRNA-126-5p nanoparticles to septic animals significantly improved survival, preserved vascular integrity, and modulated
cytokine production. These composite studies support the concept that DEAC-pGlcNAc nanoparticles are an effective platform for delivering
miRNAs and that they may provide therapeutic benefit in
sepsis.