Daily Sepsis Research Analysis
Analyzed 42 papers and selected 3 impactful papers.
Summary
Analyzed 42 papers and selected 3 impactful articles.
Selected Articles
1. Lysosome self-sorting nanodegraders for hepatic clearance of pathogenic serum mediators.
This preclinical study introduces stiffness-oriented lysosome self-sorting nanodegraders (SOLIDs) that capture and direct serum immune mediators to hepatic lysosomes for degradation. IL-6-targeting SOLIDs reduced circulating IL-6 by an additional 70% over antibody therapy and improved 7-day survival from 0% to 66.7% in murine sepsis, highlighting a fundamentally new therapeutic modality for cytokine-driven sepsis.
Impact: Demonstrates a first-in-class extracellular protein degradation strategy with dramatic survival benefit in sepsis models and mechanistic insight into organelle targeting by nanoparticle mechanics.
Clinical Implications: If safety and translational feasibility are confirmed, SOLIDs could complement or surpass cytokine-neutralizing antibodies for rapid cytokine clearance in hyperinflammatory sepsis. This platform may enable precision depletion of circulating mediators (e.g., IL-6) to modulate cytokine storm.
Key Findings
- Rigid-core SOLIDs achieved near-quantitative lysosomal accumulation across cell types and liver-predominant biodistribution via controlled protein corona.
- IL-6-capturing SOLIDs reduced serum IL-6 by an additional ~70% compared to IL-6 antibody therapy.
- In murine sepsis, 7-day survival increased from 0% to 66.7% with IL-6-targeting SOLIDs.
- CpG-capturing SOLIDs decreased pulmonary immune cell infiltration 1.7-fold in acute lung injury and suppressed co-stimulatory molecule expression.
Methodological Strengths
- Mechanistic validation across multiple models with quantitative survival benefit in vivo.
- Platform engineering with defined analytical behavior (organelle targeting via nanoparticle mechanics).
Limitations
- Preclinical animal models; human safety, immunogenicity, and pharmacokinetics are unknown.
- Target specificity and off-target clearance of beneficial mediators require thorough profiling.
Future Directions: Toxicology, dose-finding, and biodistribution studies in large animals; expansion to other sepsis mediators (e.g., HMGB1, TNF-α); and early-phase clinical trials assessing rapid cytokine clearance and organ support endpoints.
Extracellular targeted protein degradation is an emerging therapeutic strategy but has been rarely explored for clearing circulating pathogenic mediators. Here we report stiffness-oriented lysosome self-sorting nanodegraders (SOLIDs) for hepatic lysosomal degradation of serum immune mediators. SOLIDs feature a rigid semiconducting polymer core that is revealed for the first time to confer near-quantitative lysosomal accumulation across diverse cell types. After surface bioconjugation, SOLIDs capture the immune mediators of interest from blood via controlled protein corona formation. The resulting corona composition directs biodistribution, producing predominant accumulation in the liver, where they get degraded in hepatic lysosomes. We show that IL-6-capturing SOLIDs reduced serum IL-6 by an additional 70% versus IL-6 antibody therapy and increased 7-day survival in a murine sepsis model from 0% to 66.7%. In an acute lung injury model, CpG-capturing SOLIDs reduced pulmonary immune cell infiltration 1.7-fold relative to CpG neutralization and suppressed expression of co-stimulatory molecules. This work identifies nanoparticle mechanics as a critical factor in organelle targeting and proposes a nano-therapeutic approach for the degradation of pathogenic serum biomolecules.
2. DLL4+ Neutrophils Induce Alveolar Macrophages to Cause ADAM-17-mediated Endothelial Barrier Disruption and the Increase of ICAM1hiCXCR1lo Neutrophils in Sepsis.
In CLP-induced sepsis, DLL4+ neutrophils activate alveolar macrophages via Notch1 to upregulate ADAM17, which cleaves endothelial JAM-C, disrupts the pulmonary vascular barrier, and promotes ICAM1hiCXCR1lo reverse-migrated neutrophils. Pharmacologic ADAM17 inhibition and a novel DLL4–Notch1 inhibitory peptide (NDI) restored JAM-C and reduced pathogenic neutrophil accumulation, nominating the DLL4–Notch1–ADAM17 axis as a druggable pathway.
Impact: Defines a mechanistic neutrophil–macrophage–endothelium axis in sepsis and provides first-in-class peptide inhibition of DLL4–Notch1 signaling with endothelial barrier rescue.
Clinical Implications: Suggests therapeutic avenues targeting DLL4–Notch1 or ADAM17 to prevent pulmonary endothelial leak and limit harmful reverse-migrated neutrophils in sepsis-associated lung injury.
Key Findings
- DLL4+ neutrophils engaged Notch1 on alveolar macrophages, increasing ADAM17 expression in CLP sepsis.
- ADAM17 reduced endothelial JAM-C on PVECs, disrupting barrier integrity and promoting ICAM1hiCXCR1lo neutrophils.
- An ADAM17 inhibitor preserved endothelial barrier integrity and reduced pathogenic neutrophil accumulation.
- A novel DLL4–Notch1 inhibitory peptide (NDI) suppressed ADAM17, restored JAM-C, and decreased ICAM1hiCXCR1lo neutrophils.
Methodological Strengths
- Integrated in vivo CLP model with cellular co-culture and protein assays (Western blot, flow cytometry).
- Pharmacologic validation using an ADAM17 inhibitor and a newly developed DLL4–Notch1 inhibitory peptide.
Limitations
- Preclinical nature without human validation of the axis or peptide.
- Safety, pharmacokinetics, and off-target effects of NDI are not characterized.
Future Directions: Quantify DLL4+ and ICAM1hiCXCR1lo neutrophils and soluble JAM-C in human sepsis cohorts; develop ADAM17/Notch1-targeted therapeutics with toxicity profiling; explore lung-specific delivery.
Sepsis remains a leading cause of death. Reverse migrated (RM) neutrophils, characterized as ICAM1hiCXCR1lo, have been recognized as a key driver of systemic inflammation and organ injury in sepsis. We have recently discovered a distinct DLL4+ subset of neutrophils that accumulate in the lungs, contributing to lung injury; however, the underlying mechanism is less understood. In sepsis, ICAM1hiCXCR1lo neutrophils, being hyperactive, were shown to be detrimental. Here, we investigated how DLL4+ neutrophils activate alveolar macrophages (AMs) to cause endothelial cell barrier disruption and promote neutrophil reverse migration. AMs were treated with DLL4+ neutrophils or recombinant mouse DLL4 (rmDLL4), and a disintegrin and metalloprotease (ADAM17) generated by AMs was assessed at both mRNA and protein levels. Conditioned medium was subsequently applied to pulmonary vascular endothelial cells (PVECs); junctional adhesion molecule-C (JAM-C) protein was detected by Western blot assays, and ICAM1hiCXCR1lo neutrophils were detected by flow cytometry. We demonstrate that during sepsis induced by cecal ligation and puncture (CLP), DLL4+ neutrophils interact with AMs via the Notch1 pathway, leading to increase of ADAM17 expression. ADAM17 decreased JAM-C on PVECs, causing endothelial barrier disruption and ICAM1hiCXCR1lo neutrophils generation. Small-molecule inhibitor of ADAM17 effectively preserved pulmonary endothelial barrier integrity, and reduced ICAM1hiCXCR1lo neutrophils accumulation. Importantly, we have developed a novel DLL4-Notch1 inhibitory peptide (NDI) that effectively suppresses ADAM17 expression, restores JAM-C, and reduces ICAM1hiCXCR1lo neutrophils accumulation in sepsis. These findings identify DLL4+ neutrophils as a critical inflammatory mediator that exacerbate systemic inflammation and worsen sepsis, highlight the DLL4-Notch1-ADAM17 axis as a promising therapeutic target.
3. Nucleosome-targeted host DNA depletion enables automated plasma metagenomic sequencing for sensitive detection of bloodstream pathogens.
An automated plasma mNGS workflow incorporating nucleosome-targeted host DNA depletion reduced human cfDNA ~66-fold, boosted microbial reads ~47-fold, and achieved low LoDs (9.1–38 GE/mL for bacteria/fungi) in analytical validation. In 107 suspected BSI patients, HD-mNGS outperformed standard approaches against a composite reference, supporting scalable, standardized sepsis diagnostics.
Impact: Provides a practical, automated, and analytically validated solution to a major barrier in plasma mNGS (host cfDNA), with promising clinical performance for culture-independent BSI detection.
Clinical Implications: HD-mNGS could complement blood cultures in culture-negative or partially treated sepsis, enabling earlier organism identification and antimicrobial optimization within standardized laboratory workflows.
Key Findings
- Nucleosome-targeted host DNA depletion reduced human cfDNA background by ~66-fold and enriched microbial reads ~46.73-fold.
- Analytical LoD reached 9.1–38 GE/mL for bacteria/fungi and 283–321 GE/mL for viruses with excellent linearity.
- In 107 suspected BSI patients, automated HD-mNGS outperformed standard mNGS without host depletion and conventional testing against a composite reference.
Methodological Strengths
- End-to-end automation with defined contamination controls and head-to-head benchmarking.
- Comprehensive analytical validation (LoD, linearity, precision) plus real-world clinical cohort assessment.
Limitations
- Single-cohort size (n=107) limits precision of clinical performance estimates.
- Turnaround time, cost-effectiveness, and impact on antimicrobial stewardship/outcomes were not assessed.
Future Directions: Prospective multicenter trials to quantify clinical impact (time-to-targeted therapy, mortality), optimization for low-burden pathogens, and integration with rapid phenotypic resistance profiling.
BACKGROUND: Bloodstream infections (BSIs) are leading causes of sepsis-related mortality. Although metagenomic next-generation sequencing (mNGS) enables culture-independent pathogen detection, its clinical utility in plasma is limited by the overwhelming abundance of host cell-free DNA (cfDNA) and labor-intensive manual workflows. METHODS: A plasma host DNA depletion mNGS (HD-mNGS) assay was developed which integrated nucleosome-targeted host DNA depletion with automated DNA extraction and library preparation. Analytical performance was evaluated through limit of detection, linearity, precision, and contamination control. Clinical performance was assessed in a cohort of 107 patients with suspected BSI and benchmarked against blood culture (BC), conventional microbiological testing (CMT), and standard mNGS without host depletion, using a composite clinical reference standard. RESULTS: Nucleosome depletion markedly reduced host DNA background by an average of 66-fold, consequently enriching microbial reads by approximately 46.73-fold. The automated HD-mNGS assay exhibited robust analytical sensitivity, with limits of detection (LoD) ranging from 9.1 to 38 genome equivalents (GE) /mL for bacteria and fungi, and from 283 to 321 GE/mL for viruses and excellent linearity across tested concentrations (R CONCLUSIONS: Nucleosome-targeted host DNA depletion integrated with a fully automated mNGS platform significantly enhances microbial detection in plasma and provides a scalable approach for standardized BSI diagnostics.