Virus-like siRNA construct dynamically responsive to sequential microenvironments for potent RNA interference

Cytoplasmic transportation of therapeutic nucleic acids is deemed as an onerous task with aim of precise knockdown towards the targeted genes. Pertaining to the programed functionalities of natural virus in circumventing the biological barriers, we tailored multifaceted chemistries into manufacture of synthetic siRNA delivery vehicles in resembling the functionalities of viral vectors to dynamically tackle with a sequential of biological obstacles encountered in the journey of systemic anti-tumor RNAi therapy. Once harnessing ligands with RGD motif for specific internalization into subcellular endosomal compartments of the tumor cells, the architecture of the proposed delivery vehicles was subjected to facile transformation responsive to pH stimuli in acidic endosomal compartments. The external biocompatible PEGylation palisade was consequently detached, unveiling the cytomembrane-lytic cationic components to commit disruptive potencies to the anionic endosomal membranes for translocation of siRNA conjugates into cytosol. Eventually, liberation of active siRNA could be accomplished due to its responsiveness to the strikingly high level of glutathione in cytosol, thereby contributing to potent RNAi. Hence, our elaborated virus-mimicking platform has demonstrated significant anti-tumor efficacy through systemic administration of anti-angiogenic RNAi payloads, which inspired prosperous potentials in a variety of therapeutic applications.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

This article introduces a method for cytoplasmic transportation of therapeutic nucleic acids through mimicking viral vectors. The proposed platform utilizes ligands and pH stimuli to transform the delivery vehicles and transport siRNA into the cytosol. The virus-mimicking platform has demonstrated significant efficacy in anti-tumor therapy.