LAUSR

An mRNA gene therapy represents a potentially promising therapeutic for curing inflammatory diseases. The transient nature of the gene expression of mRNA would be expected to be beneficial for avoiding undesired side effects. Since the mRNA is a vulnerable molecule, a development of a carrier that can deliver the mRNA to the cytoplasm has a high priority. We report herein on the development of a system for delivering mRNA to the inflammatory lesion in a dextran sulfate sodium (DSS)-induced colitis model. We modulated molecular structures of an ionizable lipid, an SS-cleavable and pH-activated lipid-like material (ssPalm). Among the fatty acids investigated, oleic acid scaffolds (ssPalmO) appeared to be more biocompatible than either myristic acid or linoleic acid scaffolds with the colitis model. The structural modification of the hydrophilic head groups from linear tertiary amines to piperazine rings (ssPalmO-Paz4-C2) resulted in a more than 10-fold higher increasing in the transgene activity in inflammatory colon. The most notable observation is that the transgene activity in the inflammatory colon is significantly higher than that in liver, the major clearance organ of lipid nanoparticles. Collectively, the ssPalmO-Paz4-C2 represents a promising material for the delivery of an mRNA to inflammatory lesions.