Acute kidney injury (AKI) resulting from ischemia-reperfusion injury (IRI) is a common challenge in various clinical practices, yet effective therapies remain elusive. Endothelial injury plays a crucial role in the pathogenesis of renal IRI. Endothelial progenitor cells (EPCs) derived extracellular vesicles (EVs) hold promise as cell-free therapies for treating renal IRI; however, their efficacy is limited by low delivery efficiency. In this study, we developed neutrophils (NEs) membrane-modified EVs (N-EVs) by exploiting the natural properties of NEs to target damaged endothelium. N-EVs inherited the characteristic membrane proteins of NEs along with the biological functions of EPCs-EVs. Results from in vitro and in vivo experiments demonstrated that N-EVs significantly enhanced the targeting efficiency of EVs towards IRI kidneys via P-selectin glycoprotein ligand-1 (PSGL-1). Moreover, N-EVs effectively promoted the proliferation, migration, and tube-formation abilities of injured endothelial cells (ECs) and contributed to overall renal function improvement in IRI kidneys through targeted delivery of miR-21-5p. Additionally, N-EVs could restore damaged endothelial integrity, reduce cytokine release, and inhibit leukocyte infiltration, hence alleviating renal inflammation. In conclusion, our accessible engineering approach represents a promising strategy for treating renal IRI. Furthermore, this membrane hybrid modification can be tailored and optimized for broader applications in treating other diseases.
© 2025 The Authors.

There is still unmet demand for effective, safe, and patient-friendly anti-thrombotics to treat deep vein thrombosis (DVT) during pregnancy. Here we first engineer a bioactive amphiphile (TLH) by simultaneously conjugating Tempol and linoleic acid onto low molecular weight heparin (LMWH), which can assemble into multifunctional nanoparticles (TLH NP). In pregnant rats with DVT, TLH NP can target and dissolve thrombi, recanalize vessel occlusion, and eradicate the recurrence of thromboembolism, thereby reversing DVT-mediated intrauterine growth restriction and delayed development of fetuses. Mechanistically, therapeutic effects of TLH NP are realized by inhibiting platelet aggregation, facilitating thrombolysis, reducing local inflammation, attenuating oxidative stress, promoting endothelial repair, and increasing bioavailability. By decorating with a fibrin-binding peptide, targeting efficiency and therapeutic benefits of TLH NP are considerably improved. Importantly, LMWH nanotherapies show no toxicities to the mother and fetus at the dose 10-time higher than the examined therapeutic dosage.
© 2022. The Author(s).

Excessive inflammatory response caused by infiltration of a large number of neutrophils is one of the important features of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Lipoxin A4 (LXA4) is an important endogenous mediator in the process of inflammation resolution, which has a strong role in promoting inflammation resolution. In this study, we examined the impact of LXA4 on the pulmonary inflammatory response and the neutrophil function in ARDS rats. Our results indicated that exogenous administration of LXA4 could reduce the degree of lung injury in ARDS rats and inhibit the release of pro-inflammatory factors TNF-α and IL-1β in lung tissue homogenate. However, LXA4 has no lung protective effect on ARDS rats of neutropenia, nor can it inhibit the levels of pro-inflammatory factors TNF-α and IL-1β in lung tissue homogenate. LXA4 can inhibit the production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) in peripheral blood neutrophils of ARDS rats. At the same time, LXA4 can promote the phagocytosis of neutrophils in ARDS rats in vitro and can also promote the apoptosis of neutrophils in ARDS rats. In addition, the effect of LXA4 on the function of neutrophils in ARDS rats is mediated by its receptor ALX. LXA4 can inhibit the release of NE and MPO from neutrophils, thereby reducing the production of NETs. In summary, these findings indicate that LXA4 has a protective effect on LPS-induced ARDS rats by affecting the function of neutrophils.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Based on the gut-liver axis theory, a leaky gut can aggravate liver injury. However, clinical studies suggest that although gut mucosa damage is commonly observed in inflammatory bowel disease (IBD), it seldom leads to severe liver injury. We hypothesize that there is a hepatic barrier in the gut-liver axis, which protects the liver against gut-derived invasive factors.
Colitis was induced by dextran sulfate sodium (DSS) in eight different liver injury models in Sprague-Dawley rats. Liver sinusoidal endothelial cell (LSEC) injury was evaluated by a scanning and transmission electron microscope. Neutrophils were depleted by injection of anti-rat polymorphonuclear serum. Two pneumonia models were also induced to investigate the mechanism of neutrophil recruitment and activation. LSECs isolated from rat liver were used to investigate the effect on neutrophil recruitment and activation.
Among eight liver injury models, DSS colitis had no effect on liver injury in three models with normal LSECs. In the other five models with LSEC rupture, liver injury was significantly exacerbated by colitis, and increased hepatic neutrophil accumulation was observed. When neutrophils were depleted, colitis-induced liver injury was significantly attenuated. In pneumonia, liver injury, and colitis models, the level of CXCL1 correlated with the recruitment of neutrophils in different tissues, while DSS colitis and LSEC injury synergistically contributed to increased CXCL1 expression in the liver. In colitis-induced liver injury, neutrophils were activated in the liver. Injured LSECs showed both structural and functional changes, with significantly increased expression of CXCL1 and TNF-α under the stimulation of lipopolysaccharide (LPS). The combination of gut-derived LPS and LSEC-derived TNF-α led to the activation of neutrophils, characterized by enhanced production of reactive oxygen species, pro-inflammatory cytokines, and the formation of neutrophil extracellular traps.
LSECs constitute a vitally important barrier in the gut-liver axis, defending the liver against colitis-induced injury. When LSECs are damaged, they can turn into a pro-inflammatory pattern under the stimulation of LPS. LSEC injury and colitis-derived LPS synergistically contribute to the recruitment and activation of hepatic neutrophils. Neutrophils play a pivotal role as a downstream effector in colitis-induced liver injury.
Copyright © 2021 Wang, Zhang, Liu, Xu and Liu.

Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.
© 2021 Genentech.