Sepsis, week 28 edition

In a mouse model of lipopolysaccharide-induced acute kidney injury, vagus nerve stimulation enhanced Notch2 signaling in macrophages, reduced splenic inflammation, and protected renal tissue. Macrophage-specific Notch2 knockout attenuated these protective effects, supporting a causal role for Notch2 in the cholinergic anti-inflammatory pathway. Vagus nerve stimulation and macrophage Notch2 signaling also increased transferrin expression, linking neuroimmune regulation to iron homeostasis.

Impact: This study provides causal mechanistic evidence connecting bioelectronic neuroimmune modulation to protection from sepsis-related kidney injury. The Notch2–transferrin link introduces a potentially actionable bridge between inflammation and iron homeostasis.

Clinical Implications: The findings support further development of vagus nerve stimulation, Notch2 modulation, or transferrin/iron-directed strategies for sepsis-associated acute kidney injury. Translation requires validation in polymicrobial models and human early-phase studies.

This prospective multicentre study used high-dimensional spectral flow cytometry to characterize immune and endothelial cell subsets in 219 postoperative ICU patients. A LASSO-Cox cellular risk score integrating these features improved 90-day mortality prediction compared with SOFA and APACHE II. The findings were further supported by analyses of publicly available single-cell RNA sequencing datasets, suggesting a biologically grounded approach to precision sepsis prognostication.

Impact: The study moves sepsis prognostication beyond generic severity scores by integrating immune dysfunction and endothelial activation, two central drivers of organ failure. Its prospective multicentre design and single-cell corroboration strengthen its translational relevance.

Clinical Implications: Immune–endothelial profiling could refine early triage, identify biologically distinct postoperative sepsis phenotypes, and support selection of patients for immune-restorative or endothelial-protective trials. Streamlined assays and prospective external validation are needed before routine bedside use.

This preclinical study developed stiffness-oriented lysosome self-sorting nanodegraders that capture circulating immune mediators and direct them to hepatic lysosomes for degradation. IL-6-capturing particles reduced serum IL-6 by an additional 70% compared with antibody therapy and increased seven-day survival in a murine sepsis model from 0% to 66.7%. The platform also reduced inflammatory cell infiltration in an acute lung injury model, suggesting a new strategy for active mediator clearance rather than simple neutralization.

Impact: The platform offers a potentially paradigm-shifting approach to sepsis treatment by physically clearing pathogenic mediators from the circulation and outperforming antibody neutralization in a murine model. It also establishes nanoparticle mechanics as a determinant of lysosomal targeting and therapeutic biodistribution.

Clinical Implications: Lysosome-targeted nanodegraders could eventually provide rapid debulking of cytokines or damage-associated mediators in hyperinflammatory sepsis. Translation will require large-animal testing, assessment of off-target capture and hepatic toxicity, manufacturing optimization, and early-phase human trials.