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Alkylated RALA-Derived Peptides for Efficient Gene Delivery.

Xuelin Zhang1, Yexi Zhang1, Xi Rong1

  • 1State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. China.

Biomacromolecules
|November 13, 2024
PubMed
Summary

Modified RALA peptides show high efficiency and low toxicity for delivering nucleic acid therapeutics. These engineered peptides offer promising applications in siRNA therapy for various diseases.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Delivery Systems

Background:

  • RALA peptide is a proven platform for systemic nucleic acid therapeutic delivery.
  • Existing delivery systems require optimization for enhanced efficiency and reduced toxicity.

Purpose of the Study:

  • To engineer novel RALA-derived peptides with improved nucleic acid delivery capabilities.
  • To evaluate the efficacy and safety of these modified peptides for siRNA therapy.

Main Methods:

  • Modification of RALA peptides with N-terminal palmitic acid.
  • Amino acid substitutions and sequence truncation to optimize peptide properties.
  • Assessment of nucleic acid encapsulation, release, uptake, biocompatibility, and endolysosome escape.
  • Comparison of siRNA transfection efficiency and gene silencing rate against a commercial standard (Lipofectamine 2000).

Main Results:

  • All three engineered RALA peptides demonstrated effective nucleic acid encapsulation, release, uptake, and biocompatibility.
  • High siRNA transfection efficiency (approximately 90%) was achieved.
  • One peptide (C16-GLFWHHHARLARALARHLARALRA) exhibited superior gene silencing compared to Lipofectamine 2000.
  • Truncation and histidine substitution optimized particle size, zeta potential, and endosome escape via the proton sponge effect.
  • Phenylalanine incorporation enhanced carrier-cell interactions.

Conclusions:

  • Engineered RALA peptides are potent carriers for siRNA therapy, offering high efficiency and low toxicity.
  • These modified peptides show significant potential for treating various diseases through nucleic acid therapeutics.
  • Further development of these RALA derivatives could advance the field of gene silencing therapies.