Mapping neutrophil membrane bioactivity to therapeutic interfaces: Biology, disease targeting, and activity-guided...

Neutrophil plasma membranes encode a tightly coordinated set of bioactivities that control inflammatory trafficking, endothelial adhesion under shear, effector activation, and immune regulation. In this review, we present a membrane-centric framework that conceptualizes the neutrophil membrane as a programmable therapeutic interface integrating targeting, adhesion, and effector regulation. We delineate core membrane modules-including chemokine-sensing G protein-coupled receptors (GPCRs), selectin ligands, β2 integrins, Fcγ and complement receptors, pattern-recognition receptors (PRRs), and lipid-raft microdomains-and examine how their coordinated dynamics govern tissue targeting, adhesion kinetics, effector thresholds, and resolution. Integrating evidence from infection, sterile inflammation, autoimmunity, and cancer, we highlight how dysregulated membrane programs drive pathology, while their selective tuning enables therapeutic benefit. Building on this biology, we discuss two convergent intervention strategies: direct pharmacological modulation of neutrophil membrane signaling axes, and activity-guided engineering of neutrophil membrane-derived therapeutics, including native vesicles and membrane-coated nanomaterials. We further link key engineering parameters-such as membrane orientation, ligand density, glycan architecture, and microdomain integrity-to mechanism-based potency, safety, and translational control. By positioning the neutrophil membrane as a programmable interface rather than a static biomimetic shell, this review outlines a rational roadmap for developing predictable, dose-controlled therapies for infection, inflammatory diseases, and cancer.