Polymeric nanoparticles (NPs) have emerged as promising tools for immunomodulation in various disease contexts. The interactions between the NP surface and plasma-resident biomolecules result in the formation of a biomolecular corona (BC), which varies patient-to-patient and as a function of disease state, resulting in the concept of the personalized NP-BC. This study investigates how the progression of systemic inflammatory disease influences the NP-BC composition and its corresponding effects on innate immune cell interactions and activation profiles. Employing a murine model of systemic inflammation, the dynamic changes in plasma biomolecule composition and their corresponding NP-BC fingerprints were elucidated. An integrated multi-omics approach was developed to reveal disease state-specific alterations in innate immune cell phenotypes and modulated signaling pathways to identify and confirm key circulating biomolecules that contribute to the dynamic immunostimulatory capabilities of BCs.