Elucidating molecular regulatory rules of nanoparticle biological identity via standardized deep proteomics

The biological identity of nanoparticles is often redefined upon exposure to physiological fluids through the formation of a protein corona (PC), However, the molecular rules linking synthetic design to biological fate remain elusive owing to the fragmented and inconsistent proteomics data. Here, leveraging a standardized deep proteomic database of 42 diverse nanomaterials, we reveal the general molecular selection rules that govern the PC formation. We demonstrate that the PC is not a product of random adsorption but is shaped by strict property-dependent recruitment. First, surface charge regulates cellular uptake, with anionic nanoparticles specifically recruiting adhesion proteins to promote Itgav-mediated endocytosis, thus forming a causal charge-corona-receptor chain. Second, PEGylation engineers immune evasion by selectively depleting specific complement and coagulation factors, rather than merely preventing protein adsorption. Third, nanoparticle geometry imposes structural constraints and selects proteins based on specific physicochemical features such as lysine content. Beyond mechanistic insights, we show that material-specific PCs can rebalance the serum proteome and enable the detection of low-abundance disease biomarkers. This work shifts the paradigm from empirical description toward rule-based prediction and provides a foundational framework for rationally engineering nanomedicines with predictable and programmable biological identities.