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Peer-reviewedCC BY-NC-NDNature Communications

Integrated top-down and bottom-up proteomics enables precise characterization of proteoforms within the protein corona

  • Seyed Amirhossein Sadeghi1
  • Kun Li2
  • Yifan Yue1
  • Reyhane Tabatabaeian Nimavard1
  • Shaun Grumelot3,4
  • Amir Ata Saei5
  • Hojatollah Vali6,7
  • Fei Fang1
  • Xiaowen Liu8
  • Morteza Mahmoudi9,10
  • Liangliang Sun11
11 affiliations
  1. 1Department of Chemistry, Michigan State University, East Lansing, MI, USA
  2. 2Deming Department of Medicine, Tulane University, New Orleans, LA, USA
  3. 3Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
  4. 4Precision Health Program, Michigan State University, East Lansing, MI, USA
  5. 5Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
  6. 6Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada
  7. 7Facility for Electron Microscopy Research, McGill University, Montreal, QC, Canada
  8. 8Deming Department of Medicine, Tulane University, New Orleans, LA, USA. [email protected]
  9. 9Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA. [email protected]
  10. 10Precision Health Program, Michigan State University, East Lansing, MI, USA. [email protected]
  11. 11Department of Chemistry, Michigan State University, East Lansing, MI, USA. [email protected]
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Abstract

Precise characterization of proteins and proteoforms within the protein corona is essential for developing safer and more effective nanomedicines for diagnostic and therapeutic applications. Although the protein corona phenomenon has been recognized in nanomedicine for nearly two decades, the application of top-down proteomics to analyze proteoforms within this context has only recently gained traction. In this study, we advance proteoform-level analysis of the protein corona by integrating mass spectrometry (MS)-based top-down proteomics (TDP) and bottom-up proteomics (BUP). TDP analysis of protein corona of polystyrene nanoparticles (PSNPs) identified 3,505 proteoforms of 344 genes in human plasma samples, representing nearly 4-fold improvement in the number of proteoform and gene identifications (IDs) from protein corona of PSNPs and the largest proteoform dataset of protein corona reported so far. BUP analysis of the protein coronas identified 4,570 protein groups, 45,790 peptides, and 23,632 peptides containing modifications in the human plasma samples, representing one of the most comprehensive plasma proteome datasets from BUP to date and over 150% increase in protein IDs compared to previous PSNP-based corona studies. The combination of such large TDP and BUP datasets improves the characterization quality of nearly 35% of identified proteoforms containing mass shifts, producing a more precise proteoform landscape of protein corona. This BUP and TDP combination approach exceeds the capabilities of individual techniques for proteoform characterization in protein corona, and will eventually enhance our understanding of the protein corona and offer valuable insights into nanoparticle-biosystem interactions, as well as advancing proteoform-level biomarker discovery.

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Cite

BibTeXRIS
BibTeX
@article{sadeghi2026integrated,
  title = {{Integrated top-down and bottom-up proteomics enables precise characterization of proteoforms within the protein corona}},
  author = {Seyed Amirhossein Sadeghi and Kun Li and Yifan Yue and Reyhane Tabatabaeian Nimavard and Shaun Grumelot and Amir Ata Saei and Hojatollah Vali and Fei Fang and Xiaowen Liu and Morteza Mahmoudi and Liangliang Sun},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-74306-3},
  url = {https://doi.org/10.1038/s41467-026-74306-3},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Integrated top-down and bottom-up proteomics enables precise characterization of proteoforms within the protein corona
AU  - Seyed Amirhossein Sadeghi
AU  - Kun Li
AU  - Yifan Yue
AU  - Reyhane Tabatabaeian Nimavard
AU  - Shaun Grumelot
AU  - Amir Ata Saei
AU  - Hojatollah Vali
AU  - Fei Fang
AU  - Xiaowen Liu
AU  - Morteza Mahmoudi
AU  - Liangliang Sun
PY  - 2026
DA  - 2026/06/11
JO  - Nature Communications
DO  - 10.1038/s41467-026-74306-3
UR  - https://doi.org/10.1038/s41467-026-74306-3
AB  - Precise characterization of proteins and proteoforms within the protein corona is essential for developing safer and more effective nanomedicines for diagnostic and therapeutic applications. Although the protein corona phenomenon has been recognized in nanomedicine for nearly two decades, the application of top-down proteomics to analyze proteoforms within this context has only recently gained traction. In this study, we advance proteoform-level analysis of the protein corona by integrating mass spectrometry (MS)-based top-down proteomics (TDP) and bottom-up proteomics (BUP). TDP analysis of protein corona of polystyrene nanoparticles (PSNPs) identified 3,505 proteoforms of 344 genes in human plasma samples, representing nearly 4-fold improvement in the number of proteoform and gene identifications (IDs) from protein corona of PSNPs and the largest proteoform dataset of protein corona reported so far. BUP analysis of the protein coronas identified 4,570 protein groups, 45,790 peptides, and 23,632 peptides containing modifications in the human plasma samples, representing one of the most comprehensive plasma proteome datasets from BUP to date and over 150% increase in protein IDs compared to previous PSNP-based corona studies. The combination of such large TDP and BUP datasets improves the characterization quality of nearly 35% of identified proteoforms containing mass shifts, producing a more precise proteoform landscape of protein corona. This BUP and TDP combination approach exceeds the capabilities of individual techniques for proteoform characterization in protein corona, and will eventually enhance our understanding of the protein corona and offer valuable insights into nanoparticle-biosystem interactions, as well as advancing proteoform-level biomarker discovery.
SN  - 2041-1723
ER  -