Regulating intracellular fate of siRNA by endoplasmic reticulum membrane-decorated hybrid nanoplexes

Abstract

Most cationic vectors are difficult to avoid the fate of small interfering RNA (siRNA) degradation following the endosome-lysosome pathway during siRNA transfection. In this study, the endoplasmic reticulum (ER) membrane isolated from cancer cells was used to fabricate an integrative hybrid nanoplexes (EhCv/siRNA NPs) for improving siRNA transfection. Compared to the undecorated Cv/siEGFR NPs, the ER membrane-decorated EhCv/siRNA NPs exhibits a significantly higher gene silencing effect of siRNA in vitro and a better antitumor activity in nude mice bearing MCF-7 human breast tumor in vivo. Further mechanistic studies demonstrate that functional proteins on the ER membrane plays important roles on improving cellular uptake and altering intracellular trafficking pathway of siRNA. It is worth to believe that the ER membrane decoration on nanoplexes can effectively transport siRNA through the endosome-Golgi-ER pathway to evade lysosomal degradation and enhance the silencing effects of siRNA.

Microfluidic-Based Cationic Cholesterol Lipid siRNA Delivery Nanosystem: Highly Efficient In Vitro Gene Silencing and the Intracellular Behavior

“…Recent research disclosed that the caveolae-mediated endocytosis route could allow gene/drug-loaded nanoparticles to bypass the lysosome and smoothly reach the cytoplasm, e.g., Song et al found that caveolae-mediated endocytosis was conductive to the robust siRNA delivery of mannose-modified trimethyl chitosan-cysteine/tripolyphosphate nanoparticles through the subcellular organelle of the Golgi-complex and endoplasmic reticulum [ 42 ]. Qiu et al designed endoplasmic reticulum (ER) membrane-decorated siRNA nanoparticles to effectively transport siRNA through the endosome–Golgi–ER pathway to avoid lysosomal degradation [ 43 ]. In this study, caveolae/lipid raft-mediated pathways dominated the cell uptake mechanism of CEL/siRNA nanocomplexes, which inferred that high transfection efficiency was attributed to the cholesterol-dependent caveolae/lipid raft mediated pathways.…”

RNA Drug Delivery Using Biogenic Nanovehicles for Cancer Therapy

“…The results of the experiments show that siRNAloaded lipoplexes (Cv/siRNA NPs) and CCM decorated Cv/siRNA (ChCv/siRNA) have significant lower ER retention and higher lysosomes accumulation behavior than ER coated Cv/siRNA (EhCv/siRNA) (Figure 11A). This says that EhCv/siRNA did transport siRNA through the endosome-Golgi-ER pathway (Figure 11B), and thus avoiding the lysosomal degradation to enhance the therapeutic efficiency of siRNA (Qiu et al, 2019). As illustrated by the aforementioned systems, membranes derived from different cells possess particular properties.…”

“…Other cell membranes derived from platelets (Zhuang et al, 2020), endoplasmic reticulum (ER) (Qiu et al, 2019), and proinflammatory leukocytes (Jun et al, 2020) have also been researched for RNA delivery with specific targeting capacity.…”

Therapeutic siRNA: state of the art

“…122,123 Hence, further understanding the escape mechanism and how to enhance the escape efficiency is of great importance for siRNA drug development. Recently, Wang and colleagues 124 developed novel endoplasmic reticulum (ER) membrane-modified hybrid nanoplexes (EhCv/siRNA NPs). Compared with unmodified nanoplexes, they showed much higher RNAi activity in vitro and in vivo.…”