Controlled fusion of synthetic lipid membrane vesicles

Lipid membrane fusion is a fundamental noncovalent transformation as well as a central process in biology. The complex and highly controlled biological machinery of fusion has been the subject of intense investigation. In contrast, fewer synthetic approaches that demonstrate selective membrane fusion have been developed. Artificial recapitulation of membrane fusion is an informative pursuit in that fundamental biophysical concepts of biomembrane merger may be generally tested in a controlled reductionist system. A key concept that has emerged from extensive studies on lipid biophysics and biological membrane fusion is that selective membrane fusion derives from the coupling of surface recognition with local membrane disruption, or strain. These observations from native systems have guided the development of de novo-designed biomimetic membrane fusion systems that have unequivocally established the generality of these concepts in noncovalent chemistry. In this Account, we discuss the function and limitations of the artificial membrane fusion systems that have been constructed to date and the insights gained from their study by our group and others. Overall, the synthetic systems are highly reductionist and chemically selective, though there remain aspects of membrane fusion that are not sufficiently understood to permit designed function. In particular, membrane fusion with efficient retention of vesicular contents within the membrane-bound compartments remains a challenge. We discuss examples in which lipid mixing and some degree of vesicle-contents mixing is achieved, but the determinants of aqueous-compartment mixing remain unclear and therefore are difficult to generally implement. The ability to fully design membrane fusogenic function requires a deeper understanding of the biophysical underpinnings of membrane fusion, which has not yet been achieved. Thus, it is critical that biological and synthetic studies continue to further elucidate this biologically important process. Examination of lipid membrane fusion from a synthetic perspective can also reveal the governing noncovalent principles that drive chemically determined release and controlled mixing within nanometer-scale compartments. These are processes that figure prominently in numerous biotechnological and chemical applications. A rough guide to the construction of a functional membrane fusion system may already be assembled from the existing studies: surface-directed membrane apposition may generally be elaborated into selective fusion by coupling to a membrane-disruptive element, as observed over a range of systems that include small-molecule, DNA, or peptide fusogens. Membrane disruption may take different forms, and we briefly describe our investigation of the sequence determinants of fusion and lysis in membrane-active viral fusion peptide variants. These findings set the stage for further investigation of the critical elements that enable efficient, fully functional fusion of both membrane and aqueous compartments and the application of these principles to unite synthetic and biological membranes in a directed fashion. Controlled fusion of artificial and living membranes remains a chemical challenge that is biomimetic of native chemical transport and has a direct impact on drug delivery approaches.