Abstract
Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effects, poor clearance, low serum stability, and high toxicity. In this study, we genetically engineered a non-cationic non-viral tumor-targeted universal siRNA nanocarrier (MW 26 KDa). This protein nanocarrier consists of three function domains: a dsRNA binding domain (dsRBD) (from human protein kinase R) for any siRNA binding, 18-histidine for endosome escape, and two RGD peptides at the N- and C-termini for targeting tumor and tumor neovasculature. We showed that cloned dual-RGD-dsRBD-18his (dual-RGD) protein protects siRNA against RNases, induces effective siRNA endosomal escape, specifically targets integrin αvβ3 expressing cells in vitro, and homes siRNA to tumors in vivo. The delivered siRNA leads to target gene knockdown in the cell lines and tumor xenografts with low toxicity. This multifunctional and biomimetic siRNA carrier is biodegradable, has low toxicity, is suitable for mass production by fermentation, and is serum stable, holding great potential to provide a widely applicable siRNA carrier for tumor-targeted siRNA delivery.
Highlights
Published: 17 December 2021siRNA has emerged as an invaluable tool for studying gene functions and developing treatments for intractable diseases, such as cancer [1,2,3], viral infection [4,5], and genetic disorders [6,7]
We developed an innovative technology for aptamer-siRNA delivery by engineering a non-cationic protein-based carrier [20]
RGD4C was cloned with TNFα and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
Summary
Published: 17 December 2021siRNA has emerged as an invaluable tool for studying gene functions and developing treatments for intractable diseases, such as cancer [1,2,3], viral infection [4,5], and genetic disorders [6,7]. The advantage of siRNA over small chemical drugs is that siRNA sequences can be rapidly designed for highly specific inhibition of the target protein expression [11]. In one head-to-head comparison, siRNA knockdown of gene expression was about 100- to 1000-fold more efficient than antisense oligonucleotides (ODNs) [12]. In 2018, the FDA approved the first siRNA drug (patisiran), and in 2019, they approved the second siRNA drug (Givlaari) [13], which suggests that siRNA drugs are emerging as the third class of medicine after chemical drugs and antibodies for treating diseases by targeting the root cause. Most siRNA drugs so far have focused on targeting the liver
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