Self‐Fluorescent Reactive Oxygen Species‐Responsive Zinc(II)‐Quinoline Module Functionalized Polycations Hold Great Potentials in siRNA‐Mediated Gene Therapy

Abstract

AbstractA novel quinoline‐based thioketal‐containing zinc (II) coordinative module (Zn‐QS) is designed to transform common low‐molecular‐weight (LMW) polyethyleneimine (PEI) into a high‐performance siRNA carrier (Zn‐PQ) with self‐fluorescence and reactive oxygen species (ROS)‐responsiveness. In the multifunctional module, a quinoline derivative, frequently serving as pharmacophore, is utilized as the highly biocompatible ligand, and the Zn (II) coordinative quinoline‐based ligand also provides the robust self‐fluorescence character. And the ROS‐responsive thioketal spacer is introduced to trigger the siRNA controlled release into cytoplasm. Consequently, by the synergistic effects between Zn‐QS and LMW PEI on improving several crucial transfection‐efficiency‐related steps, the representative Zn‐PQ4 exhibits very high transfection efficiency of 1.8 and 2.5‐folds commercial Lipo2k and PEI25k in stem cell rADSC, respectively, >90% of transfection rates in a variety of conventional cell lines (3T3, HK‐2, HepG2, 293T, HeLa, PANC‐1), and 98.4% and 99.9% EGFP knockdown rates in 293T and HepG2 cells, respectively. Furthermore, Zn‐PQ4/siRNA polyplexes can circumvent various obstacles existing in systemic application to accumulate in heart, liver, and kidney and greatly silence the DNA expression in vivo. This work demonstrates the promising application prospects of the resulting efficient siRNA carriers in siRNA‐mediated gene therapy and fluorescence‐guided research.