Iron-Dexamethasone Nanoparticles Calm Overactive Neutrophils in Acute Lung Injury

Neutrophils are the immune system’s first responders, rushing to sites of infection or injury within minutes and unleashing a battery of antimicrobial weapons that include phagocytosis, degranulation, and the expulsion of DNA-based webs known as neutrophil extracellular traps. In a healthy response, these cells contain pathogens and then quietly stand down as inflammation resolves. But in severe conditions such as acute respiratory distress syndrome, or ARDS, neutrophils refuse to stand down. They flood the lungs, damage delicate alveolar tissue, and contribute to a condition that affects roughly ten percent of all intensive care patients and kills as many as 35 percent of those it strikes. Now, a team of bioengineers has developed a nanoparticle made almost entirely of the steroid dexamethasone that homes in on these overactive immune cells, delivering anti-inflammatory payload directly where it is needed while sidestepping the dangerous side effects that come with systemic steroid treatment.

The new particles, described in Bioengineering & Translational Medicine, were created by researchers at the University of Michigan who wanted to solve a persistent problem in corticosteroid therapy. Dexamethasone has shown real promise in recent clinical trials for ARDS, improving outcomes where older steroids failed. Yet those benefits typically require high doses over prolonged regimens, and they appear limited to certain patient subgroups, with some patients actually faring worse after treatment. Free dexamethasone circulating through the bloodstream also triggers well-documented systemic effects, including neutrophilia, an abnormal rise in blood neutrophil counts, and lymphopenia, the depletion of lymphocytes. The Michigan team reasoned that if the drug could be packaged so that it preferentially reached neutrophils themselves, the therapeutic effect would be concentrated at the source of tissue damage while the rest of the body would be spared.

The fabrication strategy is elegantly simple. The researchers added an iron sulfate solution dropwise into a stirred solution of dexamethasone phosphate, triggering a nucleation-and-growth process in which amorphous iron-phosphate particles form with dexamethasone incorporated throughout the particle matrix. The resulting nanoparticles, dubbed Dex NP, measured approximately 75 nanometers in diameter with a zeta potential between negative 10 and negative 20 millivolts. Scanning electron microscopy confirmed uniform particle morphology, and energy-dispersive X-ray spectroscopy mapping showed that iron and dexamethasone phosphate were evenly distributed across each particle rather than segregated into layers. There was just one problem: when these first-generation particles were incubated with human neutrophils in whole blood, the cells ignored them completely. No internalization occurred, which meant the drug delivery concept would fail before it even left the bench.

The breakthrough came from reconsidering the particle surface. Nanoparticle behavior in blood is governed largely by the protein corona, the layer of plasma proteins that adsorbs onto the particle within seconds of exposure. Albumin, the most abundant plasma protein, is a known dysopsonin, meaning its presence on a particle surface actively discourages phagocytes from engulfing it. The team hypothesized that the ionic iron within the particle matrix could be exploited to change the surface chemistry. Because iron oxide can form at temperatures as low as 200 degrees Celsius in open air, the researchers heated their particles to 200, 215, and 230 degrees and monitored how the protein corona changed. Only temperatures above 215 degrees altered protein adsorption, so 215 degrees became the standard oxidation step, transforming Dex NP into DexOx NP.

Characterization confirmed the transformation worked exactly as intended. X-ray photoelectron spectroscopy of the top 10 nanometers of the particle surface revealed a shift from ferrous to ferric iron, consistent with iron oxide formation, while Fourier transform infrared spectroscopy showed that the characteristic peaks of dexamethasone phosphate survived the heating intact. This mattered because dexamethasone begins to thermally degrade only above 200 degrees Celsius, with degradation onset at 256 degrees under controlled heating rates, and the brief oxidation window used here was measured in minutes rather than the hour-long exposures that have degraded the drug in prior polymer studies. Release assays in phosphate-buffered saline at physiological temperature showed that dexamethasone emerging from the particles remained as therapeutically active as the free drug, confirming the payload was not compromised during manufacturing.

The biological consequences of oxidation were striking. When FITC-labeled particles were incubated in whole human blood and mouse blood, flow cytometry showed a distinct fluorescence shift in the neutrophil population for DexOx NP but not for the unoxidized particles, and confocal microscopy visualized the oxidized particles sitting inside neutrophils. Protein corona analysis explained why: total adsorbed protein dropped after oxidation, with marked reductions in the albumin and transferrin bands at roughly 60 and 80 kilodaltons, proteins known to adsorb poorly to iron oxide. Meanwhile, a slight increase in bands between 150 and 200 kilodaltons suggested immunoglobulins, which activate complement and drive phagocytosis, had taken their place. Less albumin blocking the surface and more immunoglobulin flagging the particle combined to make DexOx NP irresistible to neutrophils.

Safety testing came next, and the particles passed cleanly. DexOx NP caused no hemolysis of red blood cells, did not activate platelets, and left unactivated neutrophils untouched, indicating the particles could be infused systemically without triggering the very inflammation they were designed to treat. In activated neutrophils, however, the therapeutic effect was dramatic. When lipopolysaccharide was used to simulate bacterial activation, DexOx NP preserved L-selectin, an adhesion molecule shed during neutrophil activation, reducing shedding by 68 percent. This outperformed both free dexamethasone phosphate and the poorly internalized Dex NP, neither of which changed L-selectin expression at all. The effect depended on the glucocorticoid receptor, since mifepristone, a receptor antagonist, blunted the benefit, and control experiments with plain iron oxide particles confirmed the activity came from the dexamethasone rather than the metal.

The particles also tamed NETosis, the explosive process by which activated neutrophils expel DNA and intracellular contents, which drives tissue damage in ARDS. In neutrophils stimulated with phorbol 12-myristate 13-acetate, DexOx NP reduced total NET formation by 21 percent over five hours, while free dexamethasone phosphate, unoxidized particles, and cargo-free polystyrene particles had no effect. The mechanism likely involves inhibition of NADPH oxidase, the enzyme complex that initiates NET formation and whose p47phox subunit is a known corticosteroid target. Because internalized particles release dexamethasone directly into the cytosol where the glucocorticoid receptor resides, the team suggests the intracellular delivery route accelerates and amplifies the drug’s action compared with diffusion of free steroid from the extracellular fluid.

The decisive test came in a mouse model of acute lung injury, where lipopolysaccharide was instilled into the airways and treatments were injected into the tail vein one hour later. Both DexOx NP and free dexamethasone significantly reduced immune cell infiltration into the lungs, cutting total bronchoalveolar lavage cells by 37 and 34 percent respectively and neutrophil counts by 41 and 39 percent. Both treatments lowered the inflammatory cytokines IL-6 and TNF-alpha, and DexOx NP significantly reduced KC, a chemokine that recruits neutrophils to inflamed tissue. Cargo-free polystyrene particles, which neutrophils also engulf, did nothing, proving the benefit came from the drug rather than from particle diversion alone. Crucially, the side-effect profiles diverged sharply: free dexamethasone raised blood neutrophil counts by 57 percent and increased the neutrophil-to-lymphocyte ratio by 64 percent, classic signs of systemic steroid exposure, while DexOx NP produced neither effect. Liver enzymes, leukocyte counts, and body weight remained normal in healthy mice given the particles.

The findings point toward a broader strategy for taming acute inflammation without the blunt instrument of systemic steroids. Because the particles are composed of iron and the drug itself, with no exogenous polymer carrier, they avoid the stability, reproducibility, and loading problems that plague conventional formulations such as liposomes and PLGA particles. The researchers, who have filed a patent on composite drug particles, note that the approach could extend beyond dexamethasone to other corticosteroids and inflammatory diseases driven by neutrophil dysregulation. For a condition like ARDS, where clinicians have long struggled to harness steroid power without immunological collateral damage, a nanoparticle that speaks directly to the immune system’s most volatile cells represents a meaningful step toward precision anti-inflammatory medicine.

Subject of Research: Targeted dexamethasone nanoparticles that modulate neutrophil activity to treat acute neutrophilic inflammation and acute lung injury

Article Title: Iron‐dexamethasone nanoparticles mitigate acute neutrophilic inflammation

Article References: Felder, M. L., Guevara, M. V., Kupor, D., & Eniola‐Adefeso, O. (2026). Iron‐dexamethasone nanoparticles mitigate acute neutrophilic inflammation. Bioengineering & Translational Medicine, Article e70173. https://doi.org/10.1002/btm2.70173

Image Credits: AI Generated

DOI: 10.1002/btm2.70173

Keywords: neutrophils, dexamethasone, nanoparticles, acute lung injury, ARDS, drug delivery, inflammation, NETosis, protein corona, iron oxide, corticosteroids, immunomodulation