Biocompatible Hydrogel Nanoparticles with Lysosomal Escape Properties for the Delivery of siRNA for the Gene Therapy of Colorectal Carcinoma

Although the significance of the curative effect has been recognized, ideal nanocarriers with the properties of lysosomal escape and biocompatibility are still lacking for the development of siRNA-based cancer gene therapy. In this work, a lysosomal escaped and redox-responsive polyacrylamide nanohydrogel (cRGD-9R-PA_ss) was constructed for STAT3 siRNA delivery. The functional groups, including tumor-targeting peptide cRGD, cell-penetrating and lysosome-escaping peptide 9R, and a redox-responsive disulfide bond, were introduced to the polyacrylamide nanohydrogel to attain enhanced transfection efficiency and biocompatibility. The synthesized cRGD-9R-PA_ss(siRNA) was dispersed as core–shell nanoparticles in water with an average size of 48 nm. cRGD-9R-PA_ss(siRNA) could prevent lysosomal phagocytosis and responsive release STAT3 siRNA into C26 tumor cells, thus promoting STAT3 gene silencing and inhibiting the proliferation of cancer cells in vitro and in vivo. Our results demonstrate that cRGD-9R-PA_ss hydrogel nanospheres constitute a potential candidate vector for siRNA-based colon cancer gene therapy.