Protein Coronas on Functionalized Nanoparticles Enable Quantitative and Precise Large-Scale Deep Plasma Proteomics.

Background

The wide dynamic range of circulating proteins coupled with the diversity of proteoforms present in plasma has historically impeded comprehensive and quantitative characterization of the plasma proteome at scale. Automated nanoparticle (NP) protein corona-based proteomics workflows can efficiently compress the dynamic range of protein abundances into a mass spectrometry (MS)-accessible detection range. This enhances the depth and scalability of quantitative MS-based methods, which can elucidate the molecular mechanisms of biological processes, discover new protein biomarkers, and improve comprehensiveness of MS-based diagnostics.

Methods

Investigating multi-species spike-in experiments and a cohort, we investigated fold-change accuracy, linearity, precision, and statistical power for the using the Proteograph

Results

We show that NP-based workflows enable accurate identification (false discovery rate of 1%) of more than 6,000 proteins from plasma (Orbitrap Astral) and, compared to a gold standard neat plasma workflow that is limited to the detection of hundreds of plasma proteins, facilitate quantification of more proteins with accurate fold-changes, high linearity, and precision. Furthermore, we demonstrate high statistical power for the discovery of biomarkers in small- and large-scale cohorts.

Conclusions

The automated NP workflow enables high-throughput, deep, and quantitative plasma proteomics investigation with sufficient power to discover new biomarker signatures with a peptide level resolution.

Déclaration de conflit d'intérêts

Authors Disclosure or Potential Conflict of Interest O.C.F. has financial interest in Selecta Biosciences, Tarveda Therapeutics, and Seer where he is officer/director; and he serves as Senior Lecturer at BWH/HMS. S.F., Al.St., M.H., B.T., T.R.B., T.W., E.M.E., X.Z., E.S.O., A.A., B.L., J.C., M.F., J.W., M.G., H.X., C.S., Y.H., S.B., A.S., V.F., O.C.F., D.H. have financial interest in Seer, S.F., B.T., T.R.B., T.W., E.M.E., E.S.O., X.Z., T.W., J.C., M.F., J.W., M.G., H.X., C.S., A.S., V.F., O.C.F., D.H. have financial interest in PrognomiQ. E.D., T.A., A.H. are employed by Thermo Fisher Scientific. R.W. is a consultant to ModeRNA, Lumicell, Seer, Earli, and Accure Health. All other authors declare no conflicts of interest.