SiRNA for Therapeutic Immuno-modulation: Simultaneous Delivery of Cytokine Targeted SiRNA and DNA Antigens to Dendritic Cells using Polymer Microcarriers

摘要

RNA interference mediated gene knockdown is a potential immuno-modulatory tool for tuning dendritic cells (DC) activation and function in-vivo. We have developed a novel multi-tiered delivery system for combinatorial administration of siRNA and plasmid DNA antigens in a single gene carrier system, Our hypothesis is that co-delivery of IL-10 specific siRNA along with DNA antigens to the same dendritic cells would inhibit IL-10 production, enhance DC activation, antigen presentation, and T cell response. Non-toxic, polyethyleneimine (PEI)-functionalized, poly(lactic-co-glycolic acid) (PEI-PLGA) microparticles co-delivering IL-10 siRNA and DNA antigen exhibited significantly higher (p<0.05) IL-10 gene knockdown in primary DCs, and DNA transfection, in-vitro. Mice immunized intramuscularly with (IL-10)-SiRNA-HBsAg-PEI-PLGA particles demonstrated successful "switch" towards a stronger Thl response as compared to naked DNA or HBsAg loaded PEI-PLGA treated animals.