A peptide-targeted delivery system with pH-sensitive amphiphilic cell membrane disruption for efficient receptor-mediated siRNA delivery

The efficient delivery of therapeutic siRNA into cells of interest is a critical challenge to broad application of RNAi. In this study, we developed a peptide-targeted delivery system for highly efficient receptor-mediated cellular siRNA delivery. The targeted delivery system was readily prepared by in situ functionalization of a polymerizable pH-sensitive amphiphilic surfactant, N-(1-aminoethyl)iminobis[N-(oleicyl-cysteinyl-histinyl-1-aminoethyl)propionamide] (EHCO) and self-assembly with siRNA. The intrinsic pH-sensitive amphiphilicity of EHCO at pH 5–6 was able to induce cell membrane disruption at endosomal pH and facilitate endosomal escape of the siRNA nanoparticles after internalization. The siRNA/EHCO nanoparticles and PEGylated siRNA/EHCO nanoparticles were not cytotoxic as compared to PEI/siRNA or TransFast/siRNA nanoparticles. siRNA/EHCO nanoparticles resulted in higher siRNA delivery efficiency than PEI and TransFast. The PEGylation of the siRNA/EHCO nanoparticles significantly reduced non-specific cell uptake. The incorporation of a bombesin peptide via a PEG spacer resulted in specific cellular uptake and high gene silencing efficiency in CHO-d1EGFP cells with overexpression of bombesin receptors. Receptor-mediated endocytosis and pH-sensitive amphiphilic endosomal escape are the advantageous features of the targeted siRNA delivery system for highly efficient cell-specific siRNA delivery. This novel targeted delivery system holds a great promise for systemic and targeted delivery of therapeutic siRNA.

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