Phosphatidylserine (PS) is a unique
lipid that is recognized by
the endogenetic receptor, T-cell immunoglobulin mucin protein 4 (Tim4),
and PS-containing liposomes have potential use in therapeutic applications.
We prepared PS-containing liposomes of various lipid compositions
and examined how lipid membrane fluidity affects PS recognition by
Tim4 and the resulting endocytosis efficiency into Hela cells. Surface
plasmon resonance and laurdan studies showed that increasing lipid
membrane fluidity increased the stability of the PS-Tim4 interaction
but hampered the entry of liposomes into cells. These results show
that endocytosis efficiency is determined by balancing opposing forces
induced by membrane fluidity. We found that inclusion of the zwitterionic
helper lipid, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine,
into liposomes ensured efficient cellular internalization because
the presence of this lipid provides an ideal balance of lipid fluidity
and Tim4 affinity. The results showed that PS recognition by Tim4
and the resulting endocytosis efficiency can be maximized by modulating
the membrane fluidity of liposomes by selecting a zwitterionic helper
lipid. This study improves our understanding of how to rationally
optimize nanotechnology for targeted drug delivery.
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