Neutrophil-based delivery platforms: from natural mechanisms to engineered therapeutics

Neutrophils are one of the key components of the innate immune system, and they play essential roles in various physiological processes, including phagocytosis, chemotaxis, immune sensing, and transmigration across the vascular endothelium. The synergy of neutrophil biology with nanomaterial science has led to the development of innovative neutrophil-based drug delivery systems (NDDSs) or neutrophil-derived biomimetic delivery systems. In this review, we elucidate the mechanisms underlying neutrophil-mediated targeting strategies. By utilizing inherent properties of neutrophils, targeted delivery to specific disease sites through NDDSs can be achieved. We survey various approaches for constructing NDDSs via live cell delivery strategies involving cell loading, in vivo capture, surface modification, and gene editing, as well as neutrophil-mimicking approaches based on neutrophil membranes, exosomes, and neutrophil-like cells. Manipulation of drug loading and release from NDDSs and functionalization of neutrophils allow for precise regulation and intervention of disease procession. In addition, we propose emerging approaches for novel NDDSs from an immunometabolic perspective. Finally, we address challenges and opportunities for advancing NDDSs into clinical practice.