Bioreducible Targeted Module and Chlorogenic Acid Functionalized Polycations as Efficient and Selective siRNA Vectors...

A highly efficient siRNA vector (PFS-CA) capable of selectively silencing genes in cancer cells was obtained by modifying common low-molecular-weight (LMW) polyethylenimine (PEI) with a bioreducible targeted multifunctional module (FS) to get PFS, followed by noncovalently incorporating chlorogenic acid (CA). FS combined folate receptor-mediated targeting for cancer cells with glutathione (GSH)-responsive siRNA release into the cytoplasm. CA, a highly biocompatible natural polyphenol served as a siRNA condensation enhancer, siRNA stabilizer, and ROS scavenger. Consequently, by the synergistic effects between PFS and CA, PFS-CA performs very well on several crucial siRNA delivery processes, including siRNA condensation, complex stability, cell uptake, endosome escape, and siRNA cytoplasmic release. The representative PFS4-3CA exhibited superior transfection efficiency in a variety of cancer cell lines, including neurogenic tumor-related PC12 cells, than commercial PEI_25k and Lipo_2k, and extremely high and selective gene silencing effects in cancer cells (with a gene silencing rate of 98.6% in HepG2 while only 8.4% in HK-2). Our findings demonstrated great promise for the development of a safe and effective siRNA carrier for future applications in tumor-targeted siRNA therapy.