Nanoparticle-induced gene-silencing for the suppression of inflammation

A dysregulated immune system can cause many different diseases, like inflammatory bowel diseases. In most cases the dysregulation of the transcription factor NF-κB as central regulator is involved. The treatment options are limited and coupled with severe side effects. In recent years, novel treatments like the application of nanoparticles (NPs) as carrier systems for the targeted delivery of drugs have emerged. The mechanism of RNA interference is an advantageous new therapeutic platform. The biological activity of a novel formulation of calcium phosphate NPs with incorporated p65 siRNA is assessed concerning the ability to silence NF-κB p65 expression and ameliorate inflammatory processes. The NPs are internalized in key cellular players of inflammation. The specific decoration of the NPs even increased the uptake in some cell types. The internalization process was mostly energy-dependent, and the cargo of the NPs was localized in the cytoplasm after uptake. Moreover, the p65 siRNA NPs were efficient in downregulating p65 in target cells with variably strong impact. Investigations concerning the therapeutic efficiency in a murine colitis model revealed a distinct amelioration of the local inflammation after intravenous application of the NPs with p65 siRNA. A distinct impact of the NPs on the inflammatory signaling cascade in the colon was shown. The biodistribution of the NPs was clearly influenced by the colonic inflammation with increased localization in the adjacent lymphoid organs. NPs carrying non-functional, scrambled siRNA also showed distinct impact on the colonic inflammation, while no notable off-target effects of the NPs were found in the colon of healthy mice. Here a versatile novel NP-based system for the suppression of NF-κB-mediated pro-inflammatory reactions and therefore the amelioration of colonic inflammation is demonstrated as a promising approach as a treatment of a plethora of different acute and chronic diseases in the future