The therapeutic platform, dubbed PCN, is built on a nanozyme—a synthetic nanomaterial that mimics the activity of natural enzymes. The core of the system is a hollow cerium oxide nanosphere roughly 100 nanometers in diameter, decorated with palladium nanoclusters embedded within its shell. Cerium oxide has long fascinated materials scientists because of its reversible Ce3+/Ce4+ redox cycle and abundant oxygen vacancies, which allow it to continuously scavenge reactive oxygen species, the destructive molecules that accumulate during inflammation. Unlike conventional antioxidants, which are rapidly consumed or degraded in the body, nanozymes of this kind are stable and can keep working over extended periods. The palladium decoration is not merely decorative: it fundamentally changes the catalytic chemistry of the particle.

To understand exactly how palladium boosts performance, the team turned to density functional theory calculations. These computational simulations revealed a pronounced transfer of electron density—about 2.58 elementary charges—from the palladium nanoclusters to the cerium oxide support. This electron redistribution increases the electron density at surface oxygen species and facilitates catalytic activation. Across multiple reaction pathways, palladium decoration consistently lowered the energy barriers for reactive oxygen species conversion. In the superoxide dismutase-like reaction, the palladium-loaded particles showed substantially reduced activation energies compared with pristine hollow ceria, particularly at the rate-determining step, and palladium incorporation markedly strengthened the adsorption of superoxide anions. Similar barrier reductions appeared for catalase-like activity and hydroxyl radical elimination, indicating a broad catalytic enhancement across distinct ROS-scavenging processes.

The theory held up in the laboratory. Electron spin resonance spectroscopy showed pronounced attenuation of hydroxyl radical and superoxide signals after treatment with the palladium-ceria particles, along with a marked reduction in hydrogen peroxide-associated absorbance. Importantly, cloaking the particles in neutrophil membrane did not blunt their catalytic power: the membrane-encapsulated version scavenged reactive species almost as effectively as the bare core and substantially outperformed unmodified ceria. In cell culture, the particles reduced intracellular ROS accumulation in both HT22 neurons exposed to oxidative stress and BV2 microglia stimulated with inflammatory triggers, confirming that the antioxidant activity operates inside stressed cells, not just in a test tube.

But a powerful antioxidant is useless against brain inflammation if it cannot reach the brain. The blood–brain barrier is a formidable obstacle for most nanomedicines, and this is where the design becomes truly ingenious. The researchers isolated neutrophil membranes from mice that had been stimulated with lipopolysaccharide, a bacterial molecule that provokes a strong inflammatory response. These inflammation-activated membranes carry elevated levels of adhesion proteins, including β2-integrin, CD11a, CD11b, and CD44, which neutrophils normally use to cling to activated blood vessel walls. Western blot analysis confirmed that the finished PCN particles retained these molecular determinants. Because surgery itself activates cerebrovascular endothelium—elevating adhesion molecules such as VCAM-1 and ICAM-1 in the hippocampus—the membrane cloak essentially teaches the nanoparticle to behave like a neutrophil answering an inflammatory distress call.

In vivo imaging in aged mice with surgically induced PND showed that PCN preferentially accumulated in the brain and at the surgical site, with detectable signals persisting beyond 24 hours after intravenous administration. Ex vivo imaging of brain tissue confirmed the enhanced cerebral enrichment compared with age-matched control mice. Interestingly, the particles also gathered at the tibial fracture site, suggesting they can target the peripheral inflammatory source of the syndrome as well as its cerebral consequences. Since the surgical wound serves as an important inflammatory niche that feeds signals toward the brain, this dual accumulation may help dampen the peripheral inflammatory cascade before it propagates centrally. The researchers note that this targeted distribution hints at broader potential as a modulator for systemic inflammatory diseases.

Did the treatment actually work? In an established PND model—tibial fracture with intramedullary fixation under isoflurane anesthesia in 18-month-old mice—the answer was a clear yes. In the Morris water maze, PND mice took longer to find a hidden platform, but PCN-treated mice showed significantly reduced escape latencies, and in the probe test they spent more time in the target quadrant and crossed the platform location more often. In the novel object recognition test, PCN significantly increased the discrimination index, while the uncoated palladium-ceria particles produced only a nonsignificant trend—evidence that the neutrophil membrane modification itself confers a meaningful cognitive benefit. Open-field testing ruled out changes in locomotion or anxiety as confounding factors, and swimming speeds were comparable across groups.

Underlying these behavioral improvements was a cascade of neuroprotection. PCN restored hippocampal levels of the synaptic proteins PSD95 and SYN1, thickened the postsynaptic density, and narrowed the synaptic cleft under electron microscopy. TUNEL staining revealed that the treatment markedly reduced surgery-induced neuronal apoptosis, and JC-1 assays showed partial restoration of mitochondrial membrane potential in stressed neurons. Levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, which surged in both hippocampal tissue and plasma after surgery, were robustly suppressed by PCN. Bulk RNA sequencing of hippocampal tissue added a genome-wide dimension: PCN shifted the transcriptional landscape back toward that of healthy controls, downregulating immune-inflammatory and cell death pathways—including TNF, JAK-STAT, Toll-like receptor, NOD-like receptor, and IL-17 signaling—while activating the PI3K/Akt pathway. Protein-level validation confirmed reduced phosphorylation of JAK2 and STAT3.

Perhaps the most mechanistically revealing findings concern microglial metabolism. Activated microglia in the aged hippocampus after surgery shifted toward a glycolysis-biased, pro-inflammatory state, with elevated expression of the glycolytic enzymes HK2, PFKM, PKM2, and LDHA. PCN administration suppressed this enzymatic upregulation and, in BV2 cells, downregulated the pro-inflammatory marker CD86 while upregulating the anti-inflammatory marker CD206. Seahorse extracellular flux assays showed that PCN decreased extracellular acidification rates—reflecting reduced glycolysis—while increasing oxygen consumption rates, basal and maximal respiration, and ATP production. In other words, the nanozyme pushed microglia away from the inflammatory sugar-burning mode and back toward efficient mitochondrial oxidative phosphorylation, a metabolic reprogramming that limits pro-inflammatory polarization. PCN also preserved blood–brain barrier integrity by restoring the tight junction proteins ZO-1 and occludin in hippocampal microvessels, breaking the self-amplifying loop between microglial activation, barrier breakdown, and peripheral inflammatory infiltration.

Safety data were encouraging. Hemolysis assays showed negligible red blood cell lysis across a wide concentration range, routine blood counts remained stable at 3, 7, and 14 days after administration, and liver and kidney function markers stayed within normal ranges. Histopathological examination of the brain, heart, liver, spleen, lungs, and kidneys revealed no structural abnormalities or inflammatory infiltration. The authors are candid about limitations: the work was done in aged mice, so validation in larger animals and clinically relevant surgical paradigms is still needed; other components of the neurovascular unit and upstream regulatory pathways remain to be explored; and long-term biodistribution, biodegradability, and safety require comprehensive investigation before clinical translation. Even so, the study offers a compelling proof of concept that biomimetic nanozyme therapy—combining inflammation-guided delivery, ROS detoxification, immunometabolic reprogramming, and neurovascular protection in a single particle—could one day protect the aging brain from one of surgery’s most insidious complications.

Subject of Research: A biomimetic neutrophil membrane-encapsulated palladium/ceria nanozyme for treating perioperative neurocognitive disorders in aged mice

Article Title: A Neutrophil Membrane‐Encapsulated Pd/hCeO2 Nanoformulation for Alleviating Age‐Dependent Perioperative Neurocognitive Disorders

Article References: Huang, L., Cheng, J., Xu, H., Zhang, Q., Zhang, X., Liu, Y., Zhang, Y., Dai, W., Xiong, Z., Guo, L., Xu, L., Wang, W., Xu, X., Zhou, Y., Yu, W., Li, B., Su, D., & Wen, D. (2026). A Neutrophil Membrane‐Encapsulated Pd/hCeO 2 Nanoformulation for Alleviating Age‐Dependent Perioperative Neurocognitive Disorders. Advanced Science, Article e78033. https://doi.org/10.1002/advs.78033

Image Credits: AI Generated

DOI: 10.1002/advs.78033

Keywords: nanozyme, perioperative neurocognitive disorders, neutrophil membrane, cerium oxide, palladium, blood-brain barrier, microglia, neuroinflammation, oxidative stress, glycolysis, aged mice, nanomedicine