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Yet, little is known about the interactions between NPs and proteins, and its role in enhanced depth of serum proteomics. Herein, a series of protein spike\u2010in experiments are conducted to systematically investigate protein depletion and enrichment during NPC formation. Proteomic depth is serum concentration\u2010dependent, and NPC exhibits powerful tolerance to ultra\u2010high abundant proteins. In addition, protein\u2010protein interactions (PPI), especially those involving albumin, play a pivotal role in promoting proteomic depth. Furthermore, a triple\u2010protein assay is established to interrogate the relationship between protein binding affinity and concentration. NPC formation is a product of balancing binding affinity, concentration, and PPI. Overall, this study elucidates how NPs achieve protein depletion and enrichment for enhanced serum proteomic depth to gain a better understanding of NPC as an essential tool of proteome profiling.<\/jats:p>","DOI":"10.1002\/advs.202413713","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T06:05:33Z","timestamp":1737525933000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Extreme Tolerance of Nanoparticle\u2010Protein Corona to Ultra\u2010High Abundance Proteins Enhances the Depth of Serum Proteomics"],"prefix":"10.1002","volume":"12","author":[{"given":"Qiqi","family":"Liu","sequence":"first","affiliation":[{"name":"Zhejiang Cancer Hospital Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences  Hangzhou Zhejiang 310022 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