Targeted siRNA nanocarrier: a platform technology for cancer treatment

Oncogene. 2022 Apr;41(15):2210-2224. doi: 10.1038/s41388-022-02241-w. Epub 2022 Feb 26.


The small arginine-rich protein protamine condenses complete genomic DNA into the sperm head. Here, we applied its high RNA binding capacity for spontaneous electrostatic assembly of therapeutic nanoparticles decorated with tumour-cell-specific antibodies for efficiently targeting siRNA. Fluorescence microscopy and DLS measurements of these nanocarriers revealed the formation of a vesicular architecture that requires presence of antibody-protamine, defined excess of free SMCC-protamine, and anionic siRNA to form. Only these complex nanoparticles were efficient in the treatment of non-small-cell lung cancer (NSCLC) xenograft models, when the oncogene KRAS was targeted via EGFR-mediated delivery. To show general applicability, we used the modular platform for IGF1R-positive Ewing sarcomas. Anti-IGR1R-antibodies were integrated into an antibody-protamine nanoparticle with an siRNA specifically against the oncogenic translocation product EWS/FLI1. Using these nanoparticles, EWS/FLI1 knockdown blocked in vitro and in vivo growth of Ewing sarcoma cells. We conclude that these antibody-protamine-siRNA nanocarriers provide a novel platform technology to specifically target different cell types and yet undruggable targets in cancer therapy by RNAi.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms* / genetics
  • Male
  • Oncogene Proteins, Fusion / genetics
  • Protamines / genetics
  • Protamines / metabolism
  • Proto-Oncogene Protein c-fli-1 / genetics
  • RNA, Small Interfering / genetics
  • RNA-Binding Protein EWS / genetics
  • Technology
  • Xenograft Model Antitumor Assays


  • Oncogene Proteins, Fusion
  • Protamines
  • Proto-Oncogene Protein c-fli-1
  • RNA, Small Interfering
  • RNA-Binding Protein EWS