Mirror siRNAs loading for dual delivery of doxorubicin and autophagy regulation siRNA for multidrug reversing chemotherapy

Abstract The multidrug resistance (MDR) which widely observed in multiple cancer types is responsible for the poor chemotherapy benefits of doxorubicin (Dox). Here in our study, Dox was firstly loaded into a scramble siRNA and then condensed by polyethyleneimine (PEI) 25k together with anti-autophagy siRNA, the obtained PEI/Si-D containing mirror RNAs was further coated with hyaluronic acid (HA) to shield the surface charge of PEI and offer tumor-homing property that finally developed a platform for effective cancer chemotherapy (HP/Si-D). Our results revealed that the obtained HP/Si-D was showed high stability and biocompatibility with promising transfection profile. As a result, the anti-autophagy siRNA downregulated autophagy level of target cells, which further decreased ATP supply to enhance drug retention and cell cycle arrest. These results contributed significantly to reverse the MDR of A549/Dox (Dox resistance A549 cell line) cells with promising in vitro and in vivo results, which suggested the potential of effective MDR cancer therapy using synergistic anti-autophagy and chemotherapy.