Small molecule modulation of protein corona for deep plasma proteome profiling

Ali Akbar Ashkarran, Hassan Gharibi, Seyed Amirhossein Sadeghi, Seyed Majed Modaresi, Qianyi Wang, Teng-Jui Lin, Ghafar Yerima, Ali Tamadon, Maryam Sayadi, Maryam Jafari, Zijin Lin, Danilo Ritz, David Kakhniashvili, Avirup Guha, Mohammad R. K. Mofrad, Liangliang Sun, Markita P. Landry, Amir Ata Saei () and Morteza Mahmoudi ()
Additional contact information
Ali Akbar Ashkarran: Michigan State University
Hassan Gharibi: Karolinska Institutet
Seyed Amirhossein Sadeghi: Michigan State University
Seyed Majed Modaresi: University of Basel
Qianyi Wang: Michigan State University
Teng-Jui Lin: University of California, Berkeley
Ghafar Yerima: University of California Berkeley
Ali Tamadon: University of California Berkeley
Maryam Sayadi: Michigan State University
Maryam Jafari: Karolinska Institutet
Zijin Lin: Michigan State University
Danilo Ritz: University of Basel
David Kakhniashvili: University of Tennessee Health Science Center
Avirup Guha: Medical College of Georgia at Augusta University
Mohammad R. K. Mofrad: University of California Berkeley
Liangliang Sun: Michigan State University
Markita P. Landry: University of California, Berkeley
Amir Ata Saei: Karolinska Institutet
Morteza Mahmoudi: Michigan State University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The protein corona formed on nanoparticles (NPs) has potential as a valuable diagnostic tool for improving plasma proteome coverage. Here, we show that spiking small molecules, including metabolites, lipids, vitamins, and nutrients into plasma can induce diverse protein corona patterns on otherwise identical NPs, significantly enhancing the depth of plasma proteome profiling. The protein coronas on polystyrene NPs when exposed to plasma treated with an array of small molecules allows for the detection of 1793 proteins marking an 8.25-fold increase in the number of quantified proteins compared to plasma alone (218 proteins) and a 2.63-fold increase relative to the untreated protein corona (681 proteins). Furthermore, we discovered that adding 1000 µg/ml phosphatidylcholine could singularly enable the detection of 897 proteins. At this specific concentration, phosphatidylcholine selectively depletes the four most abundant plasma proteins, including albumin, thus reducing the dynamic range of plasma proteome and enabling the detection of proteins with lower abundance. Employing an optimized data-independent acquisition approach, the inclusion of phosphatidylcholine leads to the detection of 1436 proteins in a single plasma sample. Our molecular dynamics results reveal that phosphatidylcholine interacts with albumin via hydrophobic interactions, H-bonds, and water bridges. The addition of phosphatidylcholine also enables the detection of 337 additional proteoforms compared to untreated protein corona using a top-down proteomics approach. Given the critical role of plasma proteomics in biomarker discovery and disease monitoring, we anticipate the widespread adoption of this methodology for the identification and clinical translation of biomarkers.

Date: 2024
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DOI: 10.1038/s41467-024-53966-z

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