Nucleic acids delivered by PEGylated cationic liposomes in systemic lupus erythematosus-prone mice: A possible exacerbation of lupus nephritis in the presence of pre-existing anti-nucleic acid antibodies

Abstract

Nucleic acid-based therapy with plasmid DNA (pDNA) and small interfering RNA (siRNA) have received recent attention for their ability to modulate the cellular expression of genes and proteins. Polyethylene glycol-modified (PEGylated) cationic nanoparticles have been used as non-viral vectors for the in vivo delivery of these nucleic acids. We have reported that PEGylated cationic liposomes (PCL) including pDNA or siRNA induce anti-PEG antibodies upon repeated intravenous injection, leading to the formation of immune complexes and enhanced clearance from the blood of subsequent doses. However, the issue surrounding the association of nucleic acids with PCL whether induces anti-nucleic acid antibodies has not been studied. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with the character of end-organ damage and the presence of anti-nuclear antibodies. We used a healthy mouse and an SLE mouse model to test the hypothesis that nucleic acids associated with PCL induce anti-nuclear antibodies and then induce SLE and exacerbate SLE symptoms. We report here that pDNA or siRNA associated with PCL (pDNA/PCL or siRNA/PCL) induced anti-DNA or RNA antibodies, respectively, in healthy mice. Repeated injections did not, however, cause SLE-like symptoms in the healthy mice. In addition, in SLE-prone mice with pre-existing anti-nuclear antibodies, pDNA/PCL were deposited on the kidneys and exacerbated lupus nephritis subsequent to the formation of immune complexes. These results may imply that nucleic acids associated with PCL do not contribute to the onset of SLE in healthy individuals who lack anti-nuclear antibodies, but nucleic acids may exacerbate the symptoms in SLE patients who have pre-existing anti-nuclear antibodies.