In vitro and in vivo therapeutic siRNA delivery induced by a tryptophan-rich endosomolytic peptide

Xu, Wen; Jafari, Mousa; Yuan, Feng; Ran, Pan; Chen, Baoling; Ding, Yong; Sheinin, Tatiana; D, Chu; Lu, Shan; Yuan, Yongfang; Chen, P.

doi:10.1039/c4tb00629a

Cited by 9 publications

(13 citation statements)

References 55 publications

(49 reference statements)

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“…Importantly, the knockdown was achieved with cells retaining metabolic activities over the entire incubation periods with the peptides. In contrast, transfections with Lipofectamine ® RNAiMax, which gave seemingly stronger silencing, and partly with N-TER ® , which gave similar silencing, were accompanied with impaired cell viability 40 ( Fig. 4B and Fig.…”

Section: Resultsmentioning

confidence: 95%

Autonomously folded α-helical lockers promote RNAi*

Guyader

Lamarre

Santis

et al. 2016

Sci Rep

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RNAi is an indispensable research tool with a substantial therapeutic potential. However, the complete transition of the approach to an applied capability remains hampered due to poorly understood relationships between siRNA delivery and gene suppression. Here we propose that interfacial tertiary contacts between α-helices can regulate siRNA cytoplasmic delivery and RNAi. We introduce a rationale of helical amphipathic lockers that differentiates autonomously folded helices, which promote gene silencing, from helices folded with siRNA, which do not. Each of the helical designs can deliver siRNA into cells via energy-dependent endocytosis, while only autonomously folded helices with pre-locked hydrophobic interfaces were able to promote statistically appreciable gene silencing. We propose that it is the amphipathic locking of interfacing helices prior to binding to siRNA that enables RNAi. The rationale offers structurally balanced amphipathic scaffolds to advance the exploitation of functional RNAi.

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Section: Resultsmentioning

confidence: 95%

Autonomously folded α-helical lockers promote RNAi*

Guyader

Lamarre

Santis

et al. 2016

Sci Rep

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“…In the presence of 50% serum, C6M1 protected siRNA from serum RNase degradation over a period of 24 h, compared to 4 h for the naked siRNA [78]. Moreover, C6M1:siRNA reduced tumor growth through the silencing of the anti-apoptotic protein Bcl-2 after an intratumoral injection in mice [51].…”

Section: C6 Familymentioning

confidence: 98%

Peptide-Based Nanoparticles for Therapeutic Nucleic Acid Delivery

et al. 2021

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Gene therapy offers the possibility to skip, repair, or silence faulty genes or to stimulate the immune system to fight against disease by delivering therapeutic nucleic acids (NAs) to a patient. Compared to other drugs or protein treatments, NA-based therapies have the advantage of being a more universal approach to designing therapies because of the versatility of NA design. NAs (siRNA, pDNA, or mRNA) have great potential for therapeutic applications for an immense number of indications. However, the delivery of these exogenous NAs is still challenging and requires a specific delivery system. In this context, beside other non-viral vectors, cell-penetrating peptides (CPPs) gain more and more interest as delivery systems by forming a variety of nanocomplexes depending on the formulation conditions and the properties of the used CPPs/NAs. In this review, we attempt to cover the most important biophysical and biological aspects of non-viral peptide-based nanoparticles (PBNs) for therapeutic nucleic acid formulations as a delivery system. The most relevant peptides or peptide families forming PBNs in the presence of NAs described since 2015 will be presented. All these PBNs able to deliver NAs in vitro and in vivo have common features, which are characterized by defined formulation conditions in order to obtain PBNs from 60 nm to 150 nm with a homogeneous dispersity (PdI lower than 0.3) and a positive charge between +10 mV and +40 mV.

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“…Other 2’‐OH modifications are 2’‐FANA, 2’‐EA, 2’‐O‐Allyl, 2’‐O‐CE, 2’‐O‐GE, 2’‐O‐AP, 2’‐O‐AEM and 2’‐O‐APM as shown (Figure 3). These modifications will enhance the nuclease resistance of siRNA, but they are tolerated in limited positions only [5] . Recently, Kenski et al reported that selective incorporation of 2’‐O‐benzyl and 2’‐O‐CH 2 Py modifications in siRNA will result in enhanced in vivo activity [8] …”

Section: Structural Modification Of Sirnamentioning

confidence: 99%

“…By cleaving complementary mRNA and causing post‐transcriptional gene silencing, siRNA inhibits the corresponding protein production. The most important hurdle in the application of siRNA in medicinal chemistry is the availability of efficient and safe delivery systems for siRNA [5] …”

Section: Introductionmentioning

confidence: 99%

Knocking Down Barriers: Advances in siRNA Delivery

et al. 2021

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RNA interference (RNAi) has been emerged as an effective method to silence a particular gene utilizing a sequence‐specific mechanism for gene regulation. It induces target mRNA degradation leading to a lower illness‐inducing gene product. RNAi represent a conserved mechanism. Novel concept of highly specific silencing of genes was revolutionized by the introduction of short interfering RNA (siRNA).This helped to overcome the drawbacks of RNAi and proved out to be a safer and efficient method than its counterpart finding its way into the pharmaceutical industry. Clinical trials enhanced the possibility of siRNA delivery and yielded promising results for the treatment of a wide range of illnesses but mainly for intractable diseases like cancer, inflammatory diseases, and genetic disorders. siRNA delivery methods were instrumental in developing it as a therapeutic, of which lipid encapsulation crept its way, to be a better in vivo delivery mechanism as it could be formulated effectively, being biodegradable, and has a lower toxicity level. However, the therapeutic potential of siRNA remains hampered due to a lack of a viable delivery method, a lower accuracy in tissue specificityand cytotoxicity. Hence the therapeutic usage of the method is in its budding stage. This review re‐examines the principle of siRNA, challenges in its delivery, and some recent advancesto overcome the obstacles in order to improve siRNA delivery.

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In vitro and in vivo therapeutic siRNA delivery induced by a tryptophan-rich endosomolytic peptide

Cited by 9 publications

References 55 publications

Autonomously folded α-helical lockers promote RNAi*

Autonomously folded α-helical lockers promote RNAi*

Peptide-Based Nanoparticles for Therapeutic Nucleic Acid Delivery

Knocking Down Barriers: Advances in siRNA Delivery

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