Nanoparticles for stimulation of neutrophil extracellular trap-mediated immunity

Neutrophil extracellular traps (NETs) have been identified as triggers for a self-limited inflammatory reaction upon contact with nanoparticles within our bodies. This typically results in entrapping potentially harmful nano- or micro-objects following an immune burst. The demand for potent adjuvants has led to research on particulate-based adjuvants, particularly those that act via NET formation. Various particles, including hydrophobic nanoparticles, needle-like microparticles, and other natural and artificial crystals, have been shown to induce NET formation, eliciting a robust humoral and cellular immune response toward co-injected antigens. The NET formation was found to be the basis of the efficient use of alum as a vaccine adjuvant. Thus, nanoparticles with specific surface properties serve as NET-stimulating adjuvants. In this mini-review, we aim to summarize the current knowledge about the surface properties of particulate objects and the molecular pathways involved in inducing NET formation by neutrophils. Additionally, we discuss the potential use of nanoparticles for activating neutrophils in the tissues and the exploitation of such activation for enhancing vaccine adjuvants. Upon injection, inert nano-/microparticle vaccine adjuvants are phagocytosed by macrophages, causing lysosomal damage. This initiates cytokine-based signaling, leading to neutrophil recruitment and NETosis. Neutrophil extracellular traps entrap adjuvant particles, limiting inflammation. Co-injected specific antigens, including synthetic peptides, elicit a strong immune response.image