Targeted nanocarriers for the delivery of RNAi therapeutics

RNA interference (RNAi) has the potential to reversibly silence any gene with high efficiency and specificity. To fulfill the clinical potential of RNAi, delivery vehicles are required to transport the short interfering RNA (siRNA) to the site of action in the cells of target tissues. Here, we describe the construction of novel ligand-targeted siRNA nanoparticles (NPs), co-assembled due to the complexation of alginate sulfate (AlgS) with siRNA, mediated by calcium ions bridges (AlgS–Ca2 +-siRNA NPs). Two schemes for bioconjugation of a targeting ligand were investigated; ligand bioconjugation to AlgS prior to NP co-assembly or onto the AlgS upon the NP surface. Targeting of the nanocarriers to site of action after intravenous injection was proven for 2 different ligands. Bioconjugation of N-acetylgalactosamine (GalNAc), a ligand to the asialoglycoprotein receptor (ASGPR) overexpressed on hepatocytes, showed that GalNAc-NPs were targeted to liver by a factor of ~ 3 with lesser renal clearance compared to non-targeted NPs. Bioconjugation of antibody against Periostin, a matricellular protein expressed specifically on activated fibroblasts showed targeting to fibrosis sites. Without ligand targeting, the NPs were accumulated in macrophage-enriched areas, such as after myocardial infarction. We foresee that the combined advantages of site-specific targeting and reversibility of the tri-component NPs as well as the simplicity of their fabrication make them an attractive system for targeted delivery of siRNA.