Unveiling the pitfalls of the protein corona of polymeric drug nanocarriers

The protein corona is a natural protein layer spontaneously formed around nanomaterials when exposed to biological media. This layer can alter the nanosystems' biological performance, particularly their tissue accumulation, cellular uptake, clearance by the immune system, toxicity, and even the release profile of their payloads. Hence, the characterization of this protein layer has become a critical step when developing a new nanomedicine. The modification of the nanosystem fate by the protein corona, systematically ignored in the vast majority of the nanotechnology-based research, may have contributed to the low in vitro/in vivo correlation. Actually, the protein corona of polymeric nanosystems has been scarcely studied in the literature, and most studies have been focused instead on metallic nanoparticles and liposomes. In this review, we analyzed the influence of the physicochemical properties and composition of the polymeric nanosystems on the protein layer deposited around them. In addition, we present some recommendations on how to perform the protein corona studies of polymeric nanoparticles, which, hopefully, will contribute to obtain more reliable and reproducible data in the future. Graphical abstract.