Tri-membrane nanoparticles produced by combining liposome fusion and a novel patchwork of bicelles to overcome endosomal and nuclear membrane barriers to cargo delivery

Abstract

Membrane fusion is a rational strategy for crossing intracellular membranes that present barriers to liposomal nanocarrier-mediated delivery of plasmid DNA into the nucleus of non-dividing cells, such as dendritic cells. Based on this strategy, we previously developed nanocarriers consisting of a nucleic acid core particle coated with four lipid membranes [Akita, et al., Biomaterials, 2009, 30, 2940-2949]. However, including the endosomal membrane and two nuclear membranes, cells possess three intracellular membranous barriers. Thus, after entering the nucleus, nanoparticles coated with four membranes would still have one lipid membrane remaining, and could impede cargo delivery. Until now, coating a core particle with an odd number of lipid membranes was challenging. To produce nanocarriers with an odd number of lipid membranes, we developed a novel coating method involving lipid nano-discs, also known as bicelles, as a material for packaging DNA in a carrier with an odd number of lipid membranes. In this procedure, bicelles fuse to form an outer coating that resembles a patchwork quilt, which allows the preparation of nanoparticles coated with only three lipid membranes. Moreover, the transfection activity of dendritic cells with these three-membrane nanoparticles was higher than that for nanoparticles coated with four lipid membranes. In summary, we developed novel nanoparticles coated with an odd number of lipid membranes using the novel "patchwork-packaging method" to deliver plasmid DNA into the nucleus via membrane fusion.

Cancer-Cell-Membrane-Coated Nanoparticles with a Yolk–Shell Structure Augment Cancer Chemotherapy

“…Most anticancer therapeutics, such as genotoxic agents and gene therapeutics, need to be delivered separately or concurrently to the nucleus in their active form at a sufficient concentration. , However, after cellular internalization, the majority of NPs are trapped in endocytic vesicles and transported to endosomes that undergo lysosomal fusion for degradation, leading to insufficient drug release . NPs capable of endosomal/lysosomal escape have been developed based on the proton sponge mechanism and membrane fusion. − Nevertheless, it should be noted that the cytoplasm is a net-like gel composed of microfilaments, microtubules, and organelles, which form a tenacious mesh structure . NPs that escape from endosomes/lysosomes will diffuse into the cytosolic net, where their intracellular trafficking capacity needs to be considered.…”