Decoy Nanoparticles and Protein Corona Modulation: A Novel Frontier in Sepsis Treatment

Sepsis remains a major global health challenge due to its complex pathophysiology and limited therapeutic options. Nanomedicine offers innovative strategies to address these limitations by enabling diverse nanoparticle designs and mechanisms that modulate the septic response. This review examines the dynamic interactions between nanoparticles and the immune system, with a focus on how protein corona formation shapes nanoparticle behavior, biodistribution, and therapeutic efficacy. Disease-specific protein corona profiles can serve as pathology "fingerprints" for diagnosis and targeted delivery, and their controlled formation is now emerging as a therapeutic tool rather than only a diagnostic readout. While the protein corona is a spontaneous biomolecular layer, its composition can be rationally steered to support defined therapeutic goals. In this context, decoy nanoparticles are engineered to sequester pathogens or inflammatory mediators, such as cytokines, histones, and neutrophil extracellular traps, thereby mitigating inflammation and tissue damage. This review discusses how protein corona engineering can potentiate decoy strategies in sepsis diagnosis and therapy, highlighting key platforms including macrophage‑like nanoparticles that neutralize endotoxins and cytokines, histone‑binding hydrogels, and mesoporous silica nanoparticles that scavenge cell‑free DNA and inhibit Toll‑like receptor activation. We also address how Artificial Intelligence can improve prediction of protein corona dynamics and identification of disease‑specific protein signatures, enabling more personalized nanodecoy design. Given the highly dynamic and heterogeneous nature of sepsis, characterized by evolving circulating mediators and protein profiles, integrating protein corona control with decoy mechanisms offers a multifaceted route to limit immune dysregulation, enhance drug delivery, and reduce organ damage, paving the way toward precision nanomedicine in sepsis.