Design of i-Motif DNA-Modified Liposomes: Membrane Modulation and Drug Release Control

In the controlled drug release of liposomal drug delivery systems, it is important to design functionalized liposomes based on their membrane properties in response to the external stimuli. In this study, we attempt to develop liposomal-spherical nucleic acid (LSNA), which is modified with nucleic acids on the liposomes, that would cause a pH-responsive change in the platform membrane that is effective for drug delivery. pH-responsive function was induced by modifying DNA that forms i-motifs to the lipid membrane surface of liposomes. In particular, the formation of i-motifs is expected to cause perturbation on the lipid membrane and release drugs encapsulated into liposomes. The performance of drug release can be controlled by the adjustment of the i-motif formation and membrane properties. Two types of i-motifs were selected for LSNAs to investigate whether i-motif formation of intra- and intermolecular interactions causes differences in lipid membrane perturbation and its drug release performance. Based on a series of fluorescence spectroscopy, the appropriate amount of DNA modification was determined from membrane characterization. DNA-modified liposomes showed a change in membrane fluidity depending on pH, and particularly, the fluidity of the membrane decreased under the condition of intermolecular i-motif formation. From the release pattern of liposomal-encapsulated doxorubicin, a significant increase of drug release was observed under conditions where intermolecular i-motifs were formed. Precision design based on a series of membrane characterizations has enabled optimization of LSNAs with dynamic changes for demonstrating high drug release efficacy.