Encapsulated microRNA by gemcitabine prodrug for cancer treatment.

Although microRNAs (miRNAs) function as the important tumor gene regulators, they still confront with many challenges in systemic delivery. Here, the amphiphilic gemcitabine-oleic acid prodrugs (GOA) binding miRNAs with hydrogen bond are assembled into nanoparticles (GOA/miR NPs) through hydrophobic interaction via denaturation-annealing processes and nano-precipitation technique. The non-cationic GOA/miR NPs with an average size of ~150 nm and a zeta potential of ~ - 15 mV exhibit a stable encapsulation of miRNAs with non-sequence selectivity. Either miR-122 or miR-34a encapsulated in the GOA/miR NPs is efficiently delivered into HepG2 cells and significantly downregulate the expression levels of target gene after lysosome escape and pH-responsive disassembly. Moreover, in vivo experiments demonstrate that the GOA/miR-122 NPs exhibit higher tumor accumulation. Compared to GOA micelles, GOA/miR-122 NPs displayed stronger tumor inhibition (73% regression) after intravenous injection in nude mice xenografted with HCC, along with rapid clearance in normal liver tissues. Furthermore, there is no significant influence on biochemical indicators and immune factors during the systematic administration of GOA/miR-122 NPs. The non-cationic GOA/miR NPs engineered by hydrogen bond interaction and hydrophobic forces show the enhanced synergistic antitumor efficacy and good biosafety, which will provide a potential nanomedcine for HCC treatment.