Daily Sepsis Research Analysis
Analyzed 47 papers and selected 3 impactful papers.
Summary
Three papers stand out today: a Nature Nanotechnology study introduces lysosome self-sorting nanodegraders that clear circulating mediators and dramatically improve survival in murine sepsis; a Journal of Translational Medicine paper demonstrates nucleosome-targeted host DNA depletion to automate and sensitize plasma mNGS for bloodstream pathogens; and a Journal of Leukocyte Biology study defines a DLL4–Notch1–ADAM17 axis driving endothelial barrier injury in sepsis and reports a first-in-class inhibitory peptide.
Research Themes
- Engineered nanotherapies for cytokine and DAMP clearance in sepsis
- Automated host-depleted plasma mNGS for bloodstream infection diagnosis
- Neutrophil–macrophage signaling axis (DLL4–Notch1–ADAM17) in endothelial barrier failure
Selected Articles
1. Lysosome self-sorting nanodegraders for hepatic clearance of pathogenic serum mediators.
This preclinical study introduces stiffness-oriented lysosome self-sorting nanodegraders that capture and direct serum mediators to hepatic lysosomes for degradation. IL-6-targeting nanodegraders reduced serum IL-6 an additional 70% over antibody therapy and improved 7-day survival from 0% to 66.7% in murine sepsis, with complementary benefit in an acute lung injury model.
Impact: Demonstrates a paradigm-shifting nanotherapeutic platform that outperforms antibody neutralization in sepsis models by actively clearing pathogenic mediators. Identifies nanoparticle mechanics as a determinant of organelle targeting and systemic biodistribution.
Clinical Implications: While preclinical, this approach suggests a potential therapeutic to rapidly debulk circulating cytokines/DAMPs in hyperinflammatory sepsis, possibly complementing or surpassing cytokine-directed antibodies. Safety, immunogenicity, and scalability require clinical evaluation.
Key Findings
- Rigid-core SOLIDs achieved near-quantitative lysosomal accumulation and hepatic targeting via controlled protein corona.
- IL-6-capturing SOLIDs reduced serum IL-6 by an additional ~70% compared with IL-6 antibody therapy.
- In murine sepsis, 7-day survival improved from 0% to 66.7%; CpG-capturing SOLIDs reduced lung immune infiltration 1.7-fold.
Methodological Strengths
- Multimodal validation including protein corona engineering, biodistribution, and in vivo survival endpoints.
- Head-to-head comparison against antibody therapy and evaluation in two inflammatory models (sepsis, acute lung injury).
Limitations
- Preclinical murine models; human safety, immunogenicity, and pharmacokinetics are unknown.
- Potential off-target capture and long-term hepatic effects of repeated SOLID dosing remain to be characterized.
Future Directions: Translate to large animals; define safety and immunogenicity; optimize targeting for diverse mediators; and conduct early-phase clinical trials in hyperinflammatory sepsis.
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 JAM-C on endothelial cells, disrupting barrier integrity and expanding ICAM1hiCXCR1lo neutrophils. Pharmacologic ADAM17 inhibition and a new DLL4–Notch1 inhibitory peptide reduced endothelial injury signals and pathogenic neutrophil accumulation.
Impact: Defines a mechanistic DLL4–Notch1–ADAM17 axis linking neutrophil subsets, macrophage activation, and endothelial disruption in sepsis, and introduces a targeted inhibitory peptide with therapeutic potential.
Clinical Implications: Targeting the DLL4–Notch1–ADAM17 pathway could preserve pulmonary endothelial integrity and limit harmful reverse-migrated neutrophils; ADAM17 inhibitors or peptide-based DLL4–Notch1 blockers warrant translational development.
Key Findings
- DLL4+ neutrophils engaged Notch1 on alveolar macrophages to increase ADAM17 expression.
- ADAM17 reduced endothelial JAM-C, disrupting barrier integrity and expanding ICAM1hiCXCR1lo neutrophils.
- An ADAM17 inhibitor and a novel DLL4–Notch1 inhibitory peptide (NDI) restored JAM-C and reduced pathogenic neutrophil accumulation in sepsis.
Methodological Strengths
- Integrated in vitro co-culture, molecular assays, and in vivo CLP sepsis model with pharmacologic validation.
- Cell-subset–specific mechanistic dissection linking neutrophils, macrophages, and endothelial cells.
Limitations
- Preclinical mouse models without human validation or clinical endpoints.
- Pharmacokinetics, safety, and dosing of the inhibitory peptide are not established.
Future Directions: Validate the axis and peptide in human tissues and large animals; assess safety and pharmacology; explore combination with endothelial-protective strategies.
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 host cfDNA ~66-fold and enriched microbial reads ~47-fold. Analytical LoDs were 9.1–38 GE/mL for bacteria/fungi and ~283–321 GE/mL for viruses; clinical benchmarking in 107 suspected BSI cases showed enhanced detection versus standard methods.
Impact: Provides a scalable, automated, and analytically validated plasma mNGS approach addressing a key barrier—excess host cfDNA—for culture-independent BSI diagnosis.
Clinical Implications: Host-depleted automated plasma mNGS could accelerate and broaden pathogen detection in suspected sepsis/BSI, supporting earlier targeted therapy; prospective outcome studies and turnaround-time/economic evaluations are needed for implementation.
Key Findings
- Nucleosome-targeted depletion reduced host cfDNA ~66-fold and increased microbial reads ~46.7-fold.
- Automated HD-mNGS achieved LoDs of 9.1–38 GE/mL for bacteria/fungi and 283–321 GE/mL for viruses with excellent linearity.
- In 107 suspected BSI patients, HD-mNGS outperformed standard mNGS without depletion and complemented culture/CMT under a composite clinical reference.
Methodological Strengths
- Comprehensive analytical validation (LoD, linearity, precision, contamination control) plus clinical benchmarking against multiple standards.
- Fully automated extraction and library preparation improves standardization and scalability.
Limitations
- Single-cohort size (n=107) limits precision; multi-center validation is needed.
- Clinical impact on time-to-therapy, antimicrobial stewardship, and outcomes not directly assessed.
Future Directions: Prospective multi-center diagnostic-utility and outcome trials; integration with rapid reporting pipelines; cost-effectiveness and antimicrobial stewardship impact analyses.
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