Lipid nanoparticles (LNPs) have been recognized as efficient
vehicles
to transport a large variety of therapeutics. Currently in the spotlight
as important constituents of the COVID-19 mRNA vaccines, LNPs play
a significant role in protecting and transporting mRNA to cells. As
one of their key constituents, polyethylene glycol (PEG)–lipid
conjugates are important in defining LNP physicochemical characteristics
and biological activity. PEGylation has proven particularly efficient
in conferring longer systemic circulation of LNPs, thus greatly improving
their pharmacokinetics and efficiency. Along with revealing the benefits
of PEG conjugates, studies have revealed unexpected immune reactions
against PEGylated nanocarriers such as accelerated blood clearance
(ABC), involving the production of anti-PEG antibodies at initial
injection, which initiates accelerated blood clearance upon subsequent
injections, as well as a hypersensitivity reaction referred to as
complement activation-related pseudoallergy (CARPA). Further, data
have been accumulated indicating consistent yet sometimes controversial
correlations between various structural parameters of the PEG–lipids,
the properties of the PEGylated LNPs, and the magnitude of the observed
adverse effects. Detailed knowledge and comprehension of such correlations
are of foremost importance in the efforts to diminish and eliminate
the undesirable immune reactions and improve the safety and efficiency
of the PEGylated medicines. Here, we present an overview based on
analysis of data from the CAS Content Collection regarding the PEGylated
LNP immunogenicity and overall safety concerns. A comprehensive summary
has been compiled outlining how various structural parameters of the
PEG–lipids affect the immune responses and activities of the
LNPs, with regards to their efficiency in drug delivery. This Review
is thus intended to serve as a helpful resource in understanding the
current knowledge in the field, in an effort to further solve the
remaining challenges and to achieve full potential.