Beyond Correlation: Establishing Causality in Protein Corona Formation for Nanomedicine

In contemporary studies on the role of the protein corona
in specific
biological applications, identifying correlation is
widely used to draw conclusions from observations and statistical
methods, yet it merely identifies associations without establishing
a direct influence between variables. This over reliance on observation
can lead to spurious connections where co-occurrence does not imply
causation. In contrast, a causality-focused approach
asserts the direct impact of one variable on another, offering a more
robust framework for inference and the drawing of scientific conclusions.
This approach allows researchers to better predict how changes in
a nanoparticle’s physicochemical properties or biological conditions
will affect protein corona composition and decoration, in turn affecting
their safety and therapeutic/diagnostic efficacies. As a proof of
concept, we explore the concept of “actual causality”
(introduced by Halpern and Pearl) to mathematically prove how spiking
small molecules, including metabolites, lipids, vitamins, and nutrients,
into plasma can induce diverse protein corona patterns on identical
nanoparticles. This approach significantly enhances the depth of plasma
proteome profiling. Our findings reveal that among the various spiked
small molecules, phosphatidylcholine was the actual cause of the observed
increase in the proteomic depth of the plasma sample. By considering
the concept of causality in the field of protein coronas, the nanomedicine
community can substantially improve the ability to design safer and
more efficient nanoparticles for both diagnostic and therapeutic purposes.