ATRA derived lipid nanoparticles for co-delivery of siCYP26A1 to overcome metabolic limitations of differentiation therapy in solid tumors

All-trans retinoic acid (ATRA) effectively treats acute promyelocytic leukemia but struggles in solid tumors due to insufficient tumor accumulation from poor targeting delivery and rapid metabolism by cytochrome P450 enzymes (particularly CYP26A1). Herein, we developed a lipoplex with a folic acid (F), utilizing ATRA-derived lipid nanoparticles (RA) for co-delivery of ATRA and siCYP26A1 (FRA/siCYP26A1). As the ATRA could upregulate the folate receptor β (FRβ), the endocytosis of FRA/siCYP26A1 could be consistently promoted. After FRA/siCYP26A1 treatment, the intracellular concentration of ATRA reached up to 10-fold higher than the clinically used 13-cis-retinoic acid (13-cisRA) and free ATRA. The efficient differentiation was reflected by the expression of differentiation markers peaking up to an order of magnitude higher than free ATRA and a remarkable change in cell morphology. Finally, the FRA/siCYP26A1 significantly suppressed neuroblastoma xenografts by 90.2 % and orthotopic hepatocellular carcinoma by 77.4 %. The present study, for the first time, showcased the potential of co-delivering ATRA and siRNA as a therapeutic approach to govern the concentration of ATRA in tumors and thus facilitate differentiation therapy for solid tumor treatment.