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.