Cell-penetrating poly(disulfide)-based star polymers for simultaneous intracellular delivery of miRNAs and small molecule drugs

MicroRNAs (miRNAs) are small regulatory noncoding RNAs that control a variety of biological processes. The regulation of many endogenous miRNAs is tightly associated with various diseases. Thus, the design of miRNA delivery systems with minimal endolysosomal trapping, efficient delivery and controlled miRNA release is urgently needed. Herein, we have developed a new star polymer which consists of a β-cyclodextrin (βCD) core and multiple cell-penetrating poly(disulfide) (CPD) arms. By subsequently loading the system with miRNAs and small molecule drugs, we have successfully proven that this novel drug delivery platform could efficiently enter mammalian cells (<2 h) without apparent endolysosomal trapping. The global Pearson's R value was calculated to be 0.31 between our complex and endolysosome, which is far below the threshold of >0.5 required for correlation. In addition, the GSH-triggered degradation of CPD arms and the subsequent intracellular release of miR-203 and CPT, as well as the combination therapeutic effects have been successfully demonstrated. In this way, we show that this novel platform could be used in future to minimize potential cytotoxicity encountered by many existing cationic branched polymer systems in miRNA delivery. Our results provide important starting points for using CPD-based polymers to design personalized delivery platforms.