Red Blood Cell Membrane-Camouflaged Reduction-Responsive Polyethylenimine-Based Nanoparticles for Enhanced Antitumor Efficacy of Antisense Oligonucleotides

As a potential drug, antisense oligonucleotides (AO) have considerable application prospects in the field of tumor treatment. However, the main problem to be solved is the lack of an efficient and safe carrier that contributes to reaching the target cancer cells and utilizing the antitumor effect of AO. Here, we designed and developed a novel AO delivery system, which was based on a modified polyethylenimine (PEI) named TPGS-SS-PEI by connecting tocopherol polyethylene glycol succinate (TPGS) to PEI through the disulfide bond (SS) and the biomimetic red blood cell membrane vesicles (RVs). R-TSP/AO was composed of an AO-loaded micelle (TSP/AO) as the "core" prepared by TPGS-SS-PEI, and RVs as the "shell". The formulations and properties of R-TSP/AO were optimized and characterized. The mean particle size and zeta potential of R-TSP/AO were 109.7 nm and -24.10 mV, respectively. In vitro studies indicated that R-TSP/AO was sensitive to highly reducing conditions and exhibited excellent stability and high security. In addition, R-TSP showed higher AO transfection efficiency and excellent gene silencing efficiency compared with unmodified PEI (P < 0.001). R-TSP/AO exhibited potent tumor inhibition (55.65%) in 4T1 tumor-bearing mice without inducing systemic toxicity. These findings suggested that R-TSP/AO was safe and efficient in enhancing the antitumor efficacy and R-TSP had the potential to be further researched as a carrier for nucleic acid drugs delivery.