Surface Polyethylene Glycol Conformation Influences the Protein Corona of Polyethylene Glycol-Modified Single-Walled Carbon Nanotubes: Potential Implications on Biological Performance

TLDR

Investigation of the nanoparticle protein corona, the shell of plasma proteins that forms around nanoparticles immediately after they enter the bloodstream, is a benchmark in studying nanoparticle applications across all fields of medicine, from pharmacology to toxicology. The authors report the first investigation of the protein corona adsorbed onto single‑walled carbon nanotubes modified with 2 kDa polyethylene glycol chains (PEG2‑SWCNTs) using a large‑scale gel‑based proteomics method on biological replicates. Using this proteomics approach, they selected more than 240 plasma proteins and compared their binding to PEG2‑SWCNTs with differing surface charge and PEG conformation. The study found that PEG conformation, rather than surface charge, predominantly determines the protein corona composition—coagulation, immunoglobulin, apolipoprotein, and complement proteins bind independently of protein properties—and that a mushroom‑to‑mushroom‑brush transition shortens circulation time, increases renal excretion, and shifts uptake toward the spleen, suggesting the corona mediates PEG conformation’s pharmacokinetic effects.

Abstract

Investigation of the nanoparticle protein corona, the shell of plasma proteins formed around nanoparticles immediately after they enter the bloodstream, is a benchmark in the study of the applications of nanoparticles in all fields of medicine, from pharmacology to toxicology. We report the first investigation of the protein corona adsorbed onto single-walled carbon nanotubes modified with 2 kDa molecular weight polyethylene glycol chains [PEG(2k)-modified SWCNTs or PEG2-SWCNTs] by using a large-scale gel-based proteomics method on biological replicates. More than 240 plasma proteins were selected, and their differences were analyzed among PEG2-SWCNTs differing in surface charge and PEG conformation. The protein corona of PEG2-SWCNTs showed that coagulation proteins, immunoglobulins, apolipoproteins, and proteins of the complement system were among the proteins bound by PEG2-SWCNTs and that their recruitment was independent from the isoelectric point, molecular weight, total hydrophobicity, and number of polyaromatic residues of the proteins. Statistical analysis on protein relative abundance revealed that PEG conformation had a higher influence on the PEG2-SWCNTs' protein corona repertoire than nanotube surface charge. PEG conformation also affected the biological performance of PEG2-SWCNTs. A change in PEG conformation from mushroom to mushroom-brush transition affected the competitive adsorption of the major constituents of the protein corona of PEG2-SWCNTs and promoted shorter blood circulation time, faster renal excretion, and higher relative spleen versus liver uptake of PEG2-SWCNTs. Our data suggest that the protein corona, along with steric stabilization, may mediate the action of PEG conformation on the pharmacokinetic profile of PEG-modified SWCNTs.