Natural ligand-receptor mediated loading of siRNA in milk derived exosomes

siRNA based therapeutics have become the next frontier in molecular medicine. Though exosomes emerge as a promising drug delivery vehicle for siRNAs, significant hurdle remains in finding safe and effective loading methods. Traditional methods of loading exogenous siRNAs in exosomes are marked by certain limitations like siRNA aggregation, toxicity to the cells and their high experimental cost. As an electroporation and lipofection free approach, we show that the molecular conjugate of bovine lactoferrin with polyl-L-ysine electrostatically interacts with negatively charged siRNA, wherein lactoferrin as a ligand is captured by the GAPDH present in exosomes, loading siRNA in an effortless manner. This method exhibited transfection efficiency, colocalization percentage and colocalization threshold similar to electroporation. Furthermore, efficient uptake of exosomes loaded with siRNA via conjugate in recipient cells was observed. Our current study univocally establishes chemical free and non-mechanical method for the encapsulation and intercellular delivery of siRNA for wider therapeutic applications. © 2020 Elsevier B.V.