Biological membranes are functionalized by membrane-associated
protein machinery. Membrane-associated transport processes, such as
endocytosis, represent a fundamental and universal function mediated
by membrane-deforming protein machines, by which small biomolecules
and even micrometer-size substances can be transported via encapsulation
into membrane vesicles. Although synthetic molecules that induce dynamic
membrane deformation have been reported, a molecular approach enabling
membrane transport in which membrane deformation is coupled with substance
binding and transport remains critically lacking. Here, we developed
an amphiphilic molecular machine containing a photoresponsive diazocine
core (AzoMEx) that localizes in a phospholipid membrane. Upon photoirradiation,
AzoMEx expands the liposomal membrane to bias vesicles toward outside-in
fission in the membrane deformation process. Cargo components, including
micrometer-size M13 bacteriophages that interact with AzoMEx, are
efficiently incorporated into the vesicles through the outside-in
fission. Encapsulated M13 bacteriophages are transiently protected
from the external environment and therefore retain biological activity
during distribution throughout the body via the blood following administration.
This research developed a molecular approach using synthetic molecular
machinery for membrane functionalization to transport micrometer-size
substances and objects via vesicle encapsulation. The molecular design
demonstrated in this study to expand the membrane for deformation
and binding to a cargo component can lead to the development of drug
delivery materials and chemical tools for controlling cellular activities.
Alkaloidal chiral amphiphiles composed of C2-symmetric bispyrrolidinoindoline scaffold were developed, where the configurational differences significantly influenced the chiroptical, dynamic and supramolecular properties.
Since the cellular process of endocytosis enables uptake of biomacromolecules interacting with the cell surface by outside-in vesicle fission, endocytosis-like membrane deformation is an ideal methodology for the incorporation of micrometer-size biomacromolecules into vesicles. However, such endocytosis-like vesicle fission, which requires expansion of the liposomal membrane, has never been realized using artificial liposomal systems. Here, we developed a membrane-expanding molecular machine containing a diazocine core (AzoMEx), which exhibits an opening/closing mechanical motion in response to visible light. Upon blue light irradiation, AzoMEx embedded in a 1,2-dioleoyl-sn-glycero-3-phosphocholine bilayer expanded the liposomal membrane, assembled, and eventually induced outside-in endocytosis-like fission. When this vesicle fission was induced in the presence of micrometer-size M13 phage, it was efficiently incorporated into the vesicle by interacting with AzoMEx. The encapsulated M13 phage was transiently protected from the external environment, retaining its biological activity, and thus could be distributed throughout the body after blood administration.
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