Rodlike Supramolecular Nanoassemblies of Degradable Poly(Aspartic Acid) Derivatives and Hydroxyl‐Rich Polycations for Effective Delivery of Versatile Tumor‐Suppressive ncRNAs

Abstract

The delivery of tumor-suppressive noncoding RNAs (ncRNAs) including short ncRNAs (i.e., miRNAs) and long ncRNAs (lncRNAs) is put forward to treat tumors. In this work, novel rodlike supramolecular nanoassemblies (CNC @CB[8] @ PGEA) of degradable poly(aspartic acid) (PAsp) derivatives-grafted cellulose nanocrystals (CNCs) and hydroxyl-rich polycations (ethanolamine-functionalized poly(glycidyl methacrylate), PGEA) are proposed via typical cucurbit[8]uril (CB[8])-based host-guest interactions for delivery of different ncRNAs to treat hepatocellular carcinoma (HCC). Spindly CNCs, one kind of natural polysaccharide nanoparticles, possess good biocompatibility and unique physico-chemical properties. PGEA with abundant hydroxyl groups is one promising gene carrier with low cytotoxicity. PAsp can benefit the disassembly and degradability of nanoassemblies within cells. CNC @ CB[8]@PGEA combines the different unique properties of CNC, PGEA, and PAsp. CNC @ CB[8] @ PGEA effectively complexes the expression constructs of miR-101 (plasmid pc3.0-miR-101) and lncRNA MEG3 (plasmid pc3.0-MEG3). CNC @ CB[8] @ PGEA produces much better transfection performances than PGEA-containing assembly units. In addition, the codelivery system of CNC @ CB[8] @ PGEA/(pc3.0-MEG3+pc3.0-miR-101) nanocomplexes demonstrates better efficacy in suppressing HCC than CNC @ CB[8] @ PGEA/pc3.0-MEG3 or CNC @ CB[8] @ PGEA/pc3.0-miR-101 nanocomplexes alone. Such rodlike supramolecular nanoassemblies will provide a promising means to produce efficient delivery vectors of versatile tumor-suppressive nucleic acids.

Long non-coding RNAs: From disease code to drug role

“…Therefore, gold NPs bounded with transmembrane peptide (or TAT), which have good biocompatibility, chemical inertia, multivalent effect, and easy functionalization, can promote nuclear-lncRNA-targeted ASO applications. Moreover, rod-like supramolecular nanoassemblies, combining the unique characteristics of CNC, PGEA, and PAsp, when co-transfected with MEG3 and miR101, can be condensed into nanocomposites with a particle size less than 200 nm to achieve cooperative delivery of non-coding RNAs with different sizes and enhance drug targeting and therapeutic efficacy 120 .…”

Chemical synthesis of polysaccharide–protein and polysaccharide–peptide conjugates: A review

“…The "grafting from" method is efficient due to the low steric demand of the monomer, but it is not suited to control over the primary amino acid sequence (Wibowo, Sulistio, Wong, Blencowe, & Qiao, 2014). Chitosan-, dextran-, cyclodextrin-, and cellulose-based conjugates were synthesized for degradable delivery systems (Nie et al, 2015;Song et al, 2015;Song et al, 2018).…”

The tumor therapeutic potential of long non-coding RNA delivery and targeting

“…Considering MEG3 as the recognized tumor suppressor lncRNA, Song et al. 79 tested engineered carriers to transfer MEG3 to HCC. Using cucurbit [8] uril (CB [8]), with eight methylene-linked glycoluril molecules as the host molecule to link rodlike cellulose nanocrystals (CNCs) and ethanolamine functionalized glycidyl methacrylate (PGEA), they formed a supramolecular complex for delivering lncRNA.…”