Neutrophils are the most abundant circulating leukocytes (up to 70%) and act as the first line of defense, being the first cells recruited to the site of an infection or inflammation [1]. They are generated from self-renewing hematopoietic stem cells (HSCs) in the bone marrow, and are released into the circulation at a rate of approximately 1011 cells per day. Their retention or release into the circulation is regulated by a balance between the expression of two CXC chemokine receptors: CXCR4, expressed in bone marrow stromal cells, and CXCR2, expressed in megakaryocytes and endothelial cells which bind to the chemokine (C-X-C motif) ligands CXCL12 and CXCL1/CXCL2, respectively. The downregulation of CXCR4 along with the overexpression of CXCR2 triggers the maturation of neutrophils in the bone marrow, and their subsequent release into the circulation [2,3]. Released neutrophils are almost equally distributed in circulating and marginating pools [4]. While neutrophils in the circulating pool are able to flow freely throughout the vasculature, marginated neutrophils migrate towards the periphery of blood vessels and interact with tissue- and organ-specific surface molecules (such as P/E selectin) on the endothelium using their adhesion molecules [5,6]. This interaction results in the rolling of neutrophils along the endothelium, leading to their migration towards specific organs. The balance between neutrophils in these two compartments is altered by infections or inflammation, which may require the redistribution of neutrophils back into circulation [7]. Under physiological conditions, circulating neutrophils have a half-life of about 6–8 h. The overexpression of CXCR4 on aged neutrophils leads to their clearance by the liver, spleen, and bone marrow, followed by their elimination by resident macrophages via phagocytosis [8,9]. In response to proinflammatory cytokines resulting from inflammation or infection, the short lifespan of neutrophils can be prolonged up to several days through structural and functional modifications [10,11].

Neutrophils utilize three distinct strategies for the eradication of pathogens: phagocytosis, degranulation, and the production of neutrophil extracellular traps (NETs) — a process known as NETosis [12]. Phagocytosis is a receptor-mediated recognition and defense mechanism in which a phagosome produced by the neutrophil engulfs and eliminate the pathogen. Degranulation is associated with the fusion of cytoplasmic granules to the phagosome or the plasma membrane, leading to the release of their contents. These granules contain antimicrobial proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), proteinase-3, collagenase, and lactoferrin [13,14]. In contrast, during NETosis, neutrophils release a mesh-like structure composed of modified chromatin decorated with cytoplasmic and granular antimicrobial proteins into the extracellular space. NET formation is the result of chromatin decondensation by cytoplasmic and granular enzymes such as protein arginine deiminase 4 (PAD4), NE, and MPO [15,16]. Following their translocation from azurophilic granules to the nucleus, NE and MPO proteolytically cleave the histone in a synergistic manner [[17], [18], [19]] and by irreversibly converting arginine to citrulline, PAD4 leads to a reduction of the positive charge and compactness of the DNA-histone structure and facilitates decondensation and NET formation [20]. The release of NETs enables the neutrophil to immobilize and trap pathogens, preventing their propagation and allowing their elimination [21].

Emerging evidence has revealed that neutrophils may act as a double-edged sword. In addition to their involvement in the elimination of pathogens, the excessive activation of deregulated neutrophils and the non-specific release of NETosis components may in fact contribute to the pathogenesis and evolution of a variety of health conditions such as cancer, autoimmune disorders, and inflammatory diseases [22]. Proteomic evidences suggested that NETs can vary in protein composition and their associated pathways, resulting in various biological effects [23].

As a consequence of this dual role in physiological and pathological conditions, the targeting of neutrophils and the signaling pathways involved in their tissue infiltration has been studied as a therapeutic option [24]. Nanomedicine-based drug delivery systems have the potential to overcome certain obstacles of conventional drug formulation approaches by reducing systemic toxicity, targeting specific cells of interest, improving drug half-lives, as well as preserving activity, and providing sustained release [25,26]. Localization of nanoparticles (NPs) in the intended site can be achieved by passive targeting driven by their physical and chemical properties – such as size and charge– or active targeting using surface moieties [27].

In general, two approaches for manipulating the function of neutrophils or leveraging their tropism for drug delivery can be found in the literature: in vivo strategies, and ex vivo strategies followed by re-administration. Multiple studies have demonstrated that the intrinsic ability of neutrophils to trap NPs can be used for their targeting and the modulation of neutrophil function in vivo (Fig. 1). However, to the best of our knowledge, no previous review article has addressed active and passive strategies for neutrophil targeting in the context of these variety of diseases, allowing a more comprehensive view of the topic.

This review aims to critically assess the currently available literature on the development of neutrophil-targeting NPs and in vivo neutrophil-mediated drug delivery to ameliorate the management of severe diseases. The next five sections will review the current literature on neutrophil targeting for the management of cancer, autoimmune diseases, inflammatory conditions, respiratory diseases, and stroke. Additionally, each section has been subdivided into passive vs active targeting of neutrophils.