Core, Coating, or Corona? The Importance of Considering Protein Coronas in nano-QSPR Modeling of Zeta Potential

To control stability
in a biological medium, several factors affecting
the zeta potential (ζ) of nanoparticles (NPs) must be considered,
including complex interactions between the nanostructure and the composition
of the protein corona (PC). Effective in silico methods
(based on machine learning and quantitative structure–property
relationship (QSPR) models) could help predict and characterize the
relationship between the physicochemical properties of NP and the
formation of PC and biological outcomes in the medium at an early
stage of the experiment. However, the models currently developed are
limited to simple descriptors that do not represent the complex interactions
between the core, the coating, and their PC fingerprints. To be useful,
the models developed should be described as a function of both the
structural properties determined by the core and coating of the NPs
and the biological medium determined by the formation of the protein
corona. We have developed a set of complex descriptors that describe
the quantitative relationship between the value of the zeta potential
(ζ), core, the coating of NPs, and their PC fingerprints (the
so-called nano-QSPR model). The nano-QSPR model was developed based
on a genetic algorithm using a partial least-squares regression method
(GA-PLS), which is characterized by high external predictive power
(Q2EXT = 0.89). The GA-PLS
model was developed using descriptors that describe (i) the core structure
(determined by 7 different types of polymer-based NMs in the range
of 20 different sizes), (ii) the coating structure with 7 different
functional groups, and (iii) 80 different types of protein compositions
adsorbed on the surface of the NPs. The presented study answers the
question of how complex interactions between the corona and NP determine
the zeta potential (ζ) of NP in a given medium. Moreover, our
current study is a proof-of-concept that the zeta potential of NPs
modeled on the original structure depends not only on the NPs themselves
but also on the structure and properties determined by the NP core
and coating, as well as the biological medium determined by the formation
of the protein corona. On the basis of these results, our studies
will be useful in determining the stability and mechanism of cell
uptake, toxicity, and ability to predict the zeta potential of compounds
not yet tested.