Neutrophil membrane-coated nanoparticles (NM-NPs) are nanomedicines that use neutrophil membranes as a coating layer for nanocore materials. NM-NPs have been widely applied as targeted drug delivery systems for various inflammatory diseases and cancers, such as arthritis, sepsis, ischemia-reperfusion injury, and liver fibrosis [[1], [2], [3]]. NM-NPs have significant advantages over conventional nanomedicines in biocompatibility, stability, specificity, and efficacy [4].

The targeting mechanism of NM-NPs mainly depends on the β-integrin on the neutrophil membrane, which can mimic the adhesion process of neutrophils on the inflamed endothelium and deliver drugs to the inflamed site. However, the neutrophil membrane is not only equipped with adhesion factor receptors like β-integrins but also with various chemokine receptors and inflammatory factor receptors [5]. These receptors enable neutrophils to participate extensively in the progression of inflammation. Neutrophils utilize chemokine receptors such as CXCR2 to be the first immune cells arriving at the inflammation site, cooperate with β-integrins to adhere to and penetrate the inflamed endothelial cells, and enter the inflammatory lesion [[6], [7], [8]]. Moreover, by binding to inflammatory factors through surface inflammatory cytokines receptors, neutrophils further stimulate the release of neutrophil extracellular traps (NETs) and amplify inflammatory response through initiating an inflammatory cascade reaction [6,9,10]. This inflammatory cascade can further recruit macrophages and other inflammatory cells, thereby exacerbating the inflammation progression [11]. However, not all molecules on neutrophil membranes are completely pro-inflammatory. Phosphatidylserine (PS) expressed on the inner cell membranes will translocate to the outer when neutrophils fell into apoptosis. The apoptotic neutrophils can be recognized and phagocytosed by macrophages and promote pro-inflammatory macrophages convert to anti-inflammatory macrophages, which play an important role in resolving inflammation [12,13].

Although the neutrophil membrane inherited by NM-NPs has so much potential, most of the current studies on NM-NPs still focus on the targeting delivery function brought by β-integrins, and pay less attention to other vital membrane proteins except β-integrins [14,15]. The limited studies exploring the impact of NM-NPs on inflammation only focused on the narrow cytokine receptors. For instance, Zhang et al. achieved the neutralization of inflammatory cytokines in inflammatory arthritis by exploiting the cytokine receptors on the neutrophil membrane [16]. While this work excitingly documented the potential of NM-NPs on the neutralization of inflammation, the fate of neutralized cytokines and the direct impact of NM-NPs on inflammatory cells remain largely unexplored. Most notably, it is proved that cell membranes coated nanoparticles prepared by conventional methods are composed of a mixture of inner and outer cell membranes on the surface [17]. The outer cell membrane covers the cell membrane proteins which we commonly assumed, while the inner cell membrane mainly expresses apoptotic molecular signals such as PS [13,18,19]. Therefore, it is reasonable to presume that the NM-NPs obtained by conventional methods are a complex harboring half-activated and half-apoptotic neutrophil membranes. As a nanoparticle wearing the coat of activated and apoptotic neutrophils, it is similar to a pseudo-cell without cell activity. Thus, it is very likely to rely on its inherited cell membrane proteins to affect inflammatory mediators and the fate of the inflammatory cells in the body.

In this work, we sought to investigate the impact of NM-MPs on inflammatory cells and evaluate its effect on inflammation disease outcome in LPS-induced liver inflammation model. We observed that NM-NPs could regulate inflammation not only by neutralizing inflammatory cytokines but also by acting more systematically (Fig. 1A). NM-NPs could hinder the migration of neutrophils and macrophages to the site of inflammation by sequestering chemokines and interfering with their adhesion to inflamed endothelial cells. Once delivered to the inflamed liver, NM-NPs could be engulfed by macrophages, which could be polarized to an anti-inflammatory phenotype by the PS on the NM-NPs. Meanwhile, the cytokines and chemokines captured by the NM-NPs could be degraded by the lysosomes of the phagocytes. Under these effects, NM-NPs showed significant anti-inflammatory effects on LPS-induced hepatitis in vivo without drug loading.