Structurally modulated codelivery of siRNA and Argonaute 2 for enhanced RNA interference

Abstract

Small interfering RNA (siRNA) represents a promising class of inhibitors in both fundamental research and the clinic. Numerous delivery vehicles have been developed to facilitate siRNA delivery. Nevertheless, achieving highly potent RNA interference (RNAi) toward clinical translation requires efficient formation of RNA-induced gene-silencing complex (RISC) in the cytoplasm. Here we coencapsulate siRNA and the central RNAi effector protein Argonaute 2 (Ago2) via different delivery carriers as a platform to augment RNAi. The physical clustering between siRNA and Ago2 is found to be indispensable for enhanced RNAi. Moreover, by utilizing polyamines bearing the same backbone but distinct cationic side-group arrangements of ethylene diamine repeats as the delivery vehicles, we find that the molecular structure of these polyamines modulates the degree of siRNA/Ago2-mediated improvement of RNAi. We apply this strategy to silence the oncogene STAT3 and significantly prolong survival in mice challenged with melanoma. Our findings suggest a paradigm for RNAi via the synergistic coassembly of RNA with helper proteins.

Silencing arginine kinase/integrin β1subunit by transgenic plant expressing dsRNA inhibits the development and survival of Plutella xylostella

“…30 It is worth noting that the silence efficiency of RNAi targeting multiple genes may be limited due to the insufficiency of protein components (such as Dicer-2 and Ago-2) involved in the RNAi pathway. 31,32 The mechanism of plant-mediated RNAi against insect pests need to be further studied to increase its efficacy.…”

Small RNAs – Big Players in Plant-Microbe Interactions

“…In animal-parasite interactions, the gastrointestinal parasite nematode Heligmosomoides bakeri was recently found to secrete a specific AGO protein, exWAGO, in the EVs, which may contribute to selective export of specific siRNAs (Chow et al, 2019). Co-delivery of sRNA and AGO proteins may also facilitate sRNA stability and function, which likely increases the silencing efficiency (Li et al, 2018). Selective sRNA loading and packaging into EVs has been observed in both plant and animal systems.…”

The Role of CYP450 Drug Metabolism in Precision Cardio-Oncology

“…Due to their desirable tissue penetrability and high affinity and specificity target-binding, aptamers are expected to become a widely used platform for delivery of therapeutic small RNAs [105]. Synthetic small interfering RNAs (siRNAs) are short double-stranded RNAs that contain a guiding strand that binds target mRNA more completely than miRNA and similarly limit translation of the target mRNA [106].…”