Active regulation of protein coronas for enhancing the in vivo biodistribution and metabolism of nanoparticles

Abstract

Nanomaterials inevitably acquire protein coronas upon in vivo administration. The fate of nanoparticles is dynamically influenced by the composition of these protein coronas, which significantly affects the efficacy of nanomedicines. This work introduces a novel active regulation strategy for minimizing unforeseen effects of protein coronas by pre-introduction of nanobodies (Nbs) onto nanoparticle surfaces via a site-specific approach using the flexible spacer PEG. The site-specific PEGylation of Nbs at the C-terminus facilitates outward orientation of active motifs of Nbs on the nanoparticles, and the covalent linkage of PEG between Nbs and nanoparticles creates ample space for substrate binding to the inner nanomaterials. This approach allows functional regulation of protein corona in both quantity and composition, while preserving the inherent properties of the nanomaterials. Proteomics analysis reveals significantly distinct affinities of plasma proteins to Nb-pre-modified nanoparticles, leading to notable impact on in vivo biodistribution, metabolic behavior, and immunological response. Thus, this active regulation strategy offers a precise and controlled means to influence protein corona formation, with significant therapeutic implication for nanomaterials.