The ability to fine-tune
the volume phase transition temperature
(VPTT) of thermoresponsive nanoparticles is essential to their successful
application in drug delivery. The rational design of these materials
is limited by our understanding of the impact that nanoparticle–protein
interactions have on their thermoresponsive behavior. In this work,
we demonstrate how the formation of protein corona impacts the transition
temperature values of acrylamide-based nanogels and their reversibility
characteristics, in the presence of lysozyme, given its relevance
for the ocular and intranasal administration route. Nanogels were
synthesized with N-isopropylacrylamide or N-n-propylacrylamide as backbone monomers,
methylenebis(acrylamide) (2.5–20 molar %) as a cross-linker,
and functionalized with negatively charged monomers 2-acrylamido-2-methylpropanesulfonic
acid, N-acryloyl-l-proline, or acrylic acid;
characterization showed comparable particle diameter (c.a.10 nm), but formulation-dependent thermoresponsive properties, in
the range 28–54 °C. Lysozyme was shown to form a complex
with the negatively charged nanogels, lowering their VPTT values;
the hydrophilic nature of the charged comonomer controlled the drop
in VPTT upon complex formation, while matrix rigidity only had a small,
yet significant effect. The cross-linker content was found to play
a major role in determining the reversibility of the temperature-dependent
transition of the complexes, with only 20 molar % cross-linked-nanogels
displaying a fully reversible transition. These results demonstrate
the importance of evaluating protein corona formation in the development
of drug delivery systems based on thermoresponsive nanoparticles.