In this study, we designed and synthesized a biodegradable dendronized polypeptide (denpol) platform for delivery of small interfering RNA (siRNA). The novel denpol architecture combines the multivalency of dendrimers and conformational flexibility of linear polymers for optimal siRNA binding. Multifunctional amino acids were incorporated onto the dendrons and the structure was tuned both systematically and combinatorially to select optimal vectors. By screening a focused library, we identified several denpols that can effectively deliver siRNA to NIH 3T3 cells in vitro and exhibit minimal toxicity. For comparison, the best-performing denpol showed significantly improved transfection efficiency over Lipofectamine in serum-containing media. Fluorescence intracellular trafficking studies indicated that amphiphilicity is important for cell uptake and that the buffering capacity of histidine facilitates endosomal membrane rupture and therefore enhances the transfection efficiency. The combination of high delivery efficiency in serum and low cytotoxicity suggests the denpol system as a promising new carrier for siRNA delivery.
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