Abstract
MIS416 is a microparticulate formulation derived from propionibacterium acnes cell wall skeletons with intrinsic adjuvant activity. Conjugates of MIS416-SS-peptide containing a disulfide linkage facilitate the cytoplasmic delivery and release of peptides in antigen-presenting cells (APCs). We hypothesized that MIS416-siRNA (small interfering RNA) conjugates, containing a disulfide linkage between MIS416 and the siRNA, would allow cytoplasmic release of siRNA in APCs. MIS416-SS-siStat3 conjugates added to cell culture medium of monolayers of DCs in culture flasks successfully targeted Stat3 mRNA in DCs in vitro without transfection, downregulating Stat3 mRNA and protein levels. These results suggest that MIS416-SS-siRNA conjugates can be used as a novel siRNA delivery system for the knockdown of mRNA levels in APCs.
Highlights
Small interfering RNAs have emerged as innovative nucleic acid-based therapies and candidates for the treatment of many diseases [1,2,3,4]
MIS416 has been described as a microparticulate vector able to deliver attached cargo to dendritic cells (DCs) and other antigen-presenting cells (APCs) [15]
Confocal microscopy using bone marrow-derived dendritic cell (BMDC) showed that MIS416-PE was readily internalized by BMDC after 1 h (Fig. 1D–F) and further MIS416-PE accumulation in the cytoplasm was observed at later time points
Summary
Small interfering RNAs (siRNAs) have emerged as innovative nucleic acid-based therapies and candidates for the treatment of many diseases [1,2,3,4]. SiRNAs are impermeable to cells, and a delivery system is required for delivery of siRNAs into the cytoplasm of target cells [7]. SiRNAs delivered to cells may become trapped in endosomes, leading to ineffective treatment due to degradation caused by specific DNAses and RNAses [8,9]. To overcome these barriers, siRNA delivery systems need to be designed with the ability to transport and deliver genetic material safely and efficiently. It is potentially desirable that the delivery vector is able to target specific cells or cell types, with low cytotoxicity
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