Mechanisms of nanoparticle-mediated siRNA transfection by melittin-derived peptides
Open accessAbstract
Traditional peptide-mediated siRNA transfection via peptide transduction domains exhibits limited cytoplasmic delivery of siRNA due to endosomal entrapment. This work overcomes these limitations with the use of membrane-destabilizing peptides derived from melittin for the knockdown of NFkB signaling in a model of adult T-cell leukemia/lymphoma. While the mechanism of siRNA delivery into the cytoplasmic compartment by peptide transduction domains has not been well studied, our analysis of melittin derivatives indicates that concurrent nanocomplex disassembly and peptide-mediated endosomolysis are crucial to siRNA transfection. Importantly, in the case of the most active derivative, p5RHH, this process is initiated by acidic pH, indicating that endosomal acidification after macropinocytosis can trigger siRNA release into the cytoplasm. These data provide general principles regarding nanocomplex response to endocytosis, which may guide the development of peptide/siRNA nanocomplex-based transfection.
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Treatment of cells with chloroquine enhanced gene silencing efficiency to around 80%, consistent with release of entrapped siRNA from late-endosomes.
“Further treatment of cells with chloroquine, an endosomolytic molecule50, enhanced gene silencing efficiency to around 80%, consistent with the release of entrapped siRNA from late-endosomes (Fig. 4c; Supplementary Fig. 7g and 7h).”
From GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain (2021) · cites this paper as [50]
Membrane fusion peptides such as GALA peptides and acid-activatable melittin have been introduced into non-viral vectors to facilitate endosomal escape.
“In addition, inspired by the mechanism of viral infection, some membrane fusion peptides, such as GALA peptides and acid-activatable melittin, have been introduced into non-viral vectors to facilitate endosomal escape [184–186].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [185]
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Self-citation
- Authors
- Hou, K. K., Pan, H., Ratner, L., Schlesinger, P. H., & Wickline, S. A.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Wickline, Samuel A.
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-09-26
- Volume
- 7
- Issue
- 10
- Pages
- 8605-8615
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- PMC
- PMC4013830
- OpenAlex
- W2095435627
- Cited by
- 95
- References
- 72
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 4 · 2023: 5 · 2022: 11 · 2021: 6 · 2020: 11 · 2019: 12 · 2018: 6 · 2017: 4 · 2016: 9 · 2015: 9 · 2014: 7
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5u01ca141541-02)
- National Heart, Lung, and Blood Institute (R01HL073646)
- National Cancer Institute (R01CA063417, U01-CA141541)
- National Institute of General Medical Sciences (T32GM007200)
- National Institute of Diabetes and Digestive and Kidney Diseases (R21DK095555, DK095555)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR056223, AR056223)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
- Keywords
- siRNA transfection, endosomal escape, macropinocytosis, endosomal acidification, NF-κB signaling, adult T-cell leukemia/lymphoma, nanoparticle-mediated gene delivery
- MeSH terms
- Amino Acid Sequence, Animals, Melitten, Molecular Sequence Data, Peptides, Endosomes, Transfection, Signal Transduction, NF-kappa B, Microscopy, Atomic Force, RNA, Small Interfering, Cell Line, Tumor, Mice, Nanoparticles
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