Abstract
Though siRNA-based therapy has achieved great progress, efficient siRNA delivery remains a challenge. Here, we synthesized a copolymer PAsp(-N=C-PEG)-PCys-PAsp(DETA) consisting of a poly(aspartate) block grafted with comb-like PEG side chains via a pH-sensitive imine bond (PAsp(-N=C-PEG) block), a poly(l-cysteine) block with a thiol group (PCys block), and a cationic poly(aspartate) block grafted with diethylenetriamine (PAsp(DETA) block). The cationic polymers efficiently complexed siRNA into polyplexes, showing a sandwich-like structure with a PAsp(-N=C-PEG) out-layer, a crosslinked PCys interlayer, and a complexing core of siRNA and PAsp(DETA). Low pH-triggered breakage of pH-sensitive imine bonds caused PEG shedding. The disulfide bond-crosslinking and pH-triggered PEG shedding synergistically decreased the polyplexes’ size from 75 nm to 26 nm. To neutralize excessive positive charges and introduce the targeting ligand, the polyplexes without a PEG layer were coated with an anionic copolymer modified with the targeting ligand lauric acid. The resulting polyplexes exhibited high transfection efficiency and lysosomal escape capacity. This study provides a promising strategy to engineer the size and surface of polyplexes, allowing long blood circulation and targeted delivery of siRNA.
Highlights
RNA interference (RNAi)-based therapy and its effector small interfering RNAhave achieved great progress [1,2,3]
Apart from local delivery of chemically modified naked small interfering RNA (siRNA), most systemic delivery methods of siRNA need the help of vectors to improve therapeutic efficacy by increasing siRNA accumulation in target tissue and reducing side effects caused by non-specific uptake [7]
The pH-sensitive PEG shedding and disulfide bond-crosslinking synergistically reduced the nanoparticle size in the following ways: (i) the crosslinking between thiol groups in the middle block PCys of different polymer strands formed the crosslinked interlayer, which decreased the size of cPEG-CD/siRNA NPs; (ii) the PEG shedding caused by low pH-triggered imide bond breakage further decreased the nanoparticles’ size; (iii) the disulfide bonds-crosslinking interlayer stabilized the nanoparticles after PEG shedding
Summary
RNA interference (RNAi)-based therapy and its effector small interfering RNA (siRNA). The dior tri-block copolymer containing the PEG block and cationic block were prepared and used in a complex with siRNA in order to form nanoparticles, with/without targeting ligands conjugated to PEG [32,33,34]. These approaches take both time and effort. The targeting ligand modified PEG was added to the surface of siRNA assemblies with cationic polymer (e.g., PEI) using a hierarchical assembly strategy [35,36] Both the size and surface engineering are necessary to ensure the long blood circulation half-life and highly efficient targeting delivery. Negatively charged copolymers with a targeting ligand lauric acid were hierarchically coated above positively charged nanoparticles, allowing long circulation and targeted delivery of siRNA (Figure 1)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
