Fusogenic lipid nanocarriers: Nature-inspired design for advanced drug delivery systems

Lipid nanocarriers are a useful tool for intracellular delivery of drugs that are otherwise unable to enter their target cells. Most of these nanocarriers are designed for an endocytotic uptake, although this route of intracellular drug delivery has a number of shortcomings. A promising alternative is fusogenic lipid nanocarriers, since by this uptake mechanism lysosomal degradation problems being associated with endocytosis can be excluded and drug release into the target cell can be synchronized with the fusion process. Various mechanisms being responsible for biological fusion events, including fertilization, exocytosis, viral infection and plasma membrane repair can be copied and transferred to nanocarriers enabling them to fuse with target cells. In particular, curvature, fluidity and surface charge of nanocarriers are key parameters for fusogenic properties. Furthermore, lipid nanocarriers can be decorated with fusogenic (poly)peptides such as viral fusion peptides or SNARE-derived lipopeptides. Within this review we provide an overview about the underlying mechanisms being responsible for cell membrane fusion processes, we demonstrate how this knowledge can be utilized for the design of fusogenic lipid nanocarriers and we summarize most promising applications of fusogenic nanocarriers for treatment of different diseases.