COVID-19 mRNA vaccines and pathological cell-cell fusion: an unintended consequence

Abstract

The Pfizer and Moderna COVID-19
vaccines are composed of lipid nanoparticles
(LNP) containing a modified messenger RNA
(mRNA) that encodes for the Spike S1 protein
[1-3]. The LNP transfection likely involves
particle engulfment by the host immune cells
due to their resemblance to apoptotic bodies,
vesicles with externalized phosphatidylserine
(ePS). As the LNPs are decorated with PSlike
ionizable phospholipids, including
1,2-distearoyl-sn-glycero-3-phosphocholine
(DSPC), they encourage human phagocytes
into internalizing them [4-6].
The LNP technology, to put it simply,
mimics viral envelopes with ePS, a universal
“eat me” signal, that directs immune cells to
engulf the particle [7,8]. However, as ePS
is also a potential “fuse me” signal, LNP
may inadvertently facilitate the formation of
pathological syncytia [9,10]. Moreover, ePS
may activate a disintegrin and metalloprotease
10 and 17 (ADAM 10)(ADAM 17), master
regulators of syncytia formation, contributing
further to the unintended consequence of cellcell
fusion [11,12].
LNP-incorporated mRNA comprises an
enormous technological success that goes
beyond vaccines, opening new avenues for
developing “smart” therapeutics that can be
delivered with pinpoint precision to specific
subcellular structures [13]. The development
of such therapeutics is anticipated to redefine
clinical pathways, including for noncommunicable
diseases. However, are these
therapies ready for worldwide application in
their present molecular form?