Neutrophil-targeted nanomedicine delivery systems: therapeutic applications and future perspectives in sepsis management

Sepsis is a systemic organ dysfunction caused by an abnormal host infection response, and its high fatality rate is closely associated with uncontrolled inflammatory storms, immunological diseases, and multi-organ failure. As essential components of innate immunity, neutrophils play a dual role in sepsis. Initially, they protect tissues by phagocytosing pathogens and releasing antibacterial substances. As the disease progresses, however, they become over-activated and exacerbate tissue damage by triggering the release of cytokine and neutrophil extracellular traps (NETs). Nanomaterials, leveraging their unique size-dependent properties, surface modifiability, and drug-loading capacity, offer a strategy to overcome the critical challenges of poor drug targeting and low bio-availability in sepsis therapy. Current studies mainly concentrate on nanomaterials targeting macrophages. However, there is limited research work on nanomaterials targeting neutrophils that have emerged as a superior therapeutic focus due to their crucial roles in sepsis progression. This review emphasizes the design principles for neutrophil-targeted nanomedicine delivery systems, including transmembrane biomimetic technology, surface receptor-specific recognition, exploiting the phagocytosis of activated neutrophils, and targeting neutrophil-derived microenvironmental signals. We elucidate the targeting mechanism, and discuss the current challenges and future research directions.