A Dual-Pipeline Lactate Removal Strategy to Reverse Vascular Hyperpermeability for the Management of Lipopolysaccharide-Induced Sepsis

Nanoscience Infectious Diseases Chemistry Medicinal Chemistry Immunology Biochemistry Life Sciences Bioengineering Medicine Basic Medical Sciences
lactate removal vascular hyperpermeability sepsis lipopolysaccharides nanohybrids inflammatory response endothelial barrier function

A Novel Dual-Pipeline Lactate Removal Strategy for Sepsis Treatment

Background

Sepsis, defined as multi-organ dysfunction caused by a dysregulated host immune response to bloodborne infection, remains a severe global public health issue. Despite advances in modern medicine, the diagnosis and treatment of sepsis pose significant challenges. Statistics indicate that sepsis claims approximately 11 million lives annually, accounting for nearly one-fifth of deaths worldwide. In intensive care units (ICUs), sepsis mortality rates remain as high as 25%-30%. Current clinical treatments focus primarily on symptomatic care, such as early fluid resuscitation and the use of broad-spectrum antibiotics. However, high mortality and morbidity persist due to factors such as antibiotic resistance, systemic immune disorders, and, most crucially, the lack of effective drugs.

Lactate, a key biomarker of sepsis, is closely associated with mortality and vascular hyperpermeability in patients. Its excessive accumulation in blood results not only from hypoxia and inflammatory cascades but also from reduced clearance due to liver and kidney dysfunction. Lactate can disrupt endothelial barrier function by targeting vascular endothelial cadherin (VE-cadherin), a key adhesion protein between endothelial cells, leading to increased vascular permeability and multi-organ dysfunction. Therefore, removing circulating lactate to stabilize vascular integrity is considered a potential therapeutic strategy for sepsis. However, methods to modulate lactate metabolism have yet to be fully explored for sepsis treatment.

Research Team & Objectives

This study, conducted by researchers from the School of Materials Science and Engineering at Tiangong University, the College of Chemistry at Qingdao University, and Jilin University, is published in the Advanced Healthcare Materials journal in 2025. It introduces a pioneering “dual-pipeline lactate removal strategy” for combating lipopolysaccharide (LPS)-induced sepsis.

The research objective was to design and develop nanomaterials capable of eliminating lactate to restore endothelial integrity and ultimately improve survival outcomes in sepsis. The core idea of this study lies in the development of a highly biocompatible nanocomposite (lox@hmno2-p[5]a) that regulates lactate through “reduction of lactate production” and “enhancement of lactate consumption.” The efficacy of this strategy was validated using a mouse sepsis model.

Study Details

1. Research Design

The research was centered on the design, synthesis, and evaluation of a novel nanocomposite (lox@hmno2-p[5]a). The details are as follows:

  • Design of Nanocomposite Structure and Functionality: The researchers employed lactate oxidase (LOX) as a catalyst for lactate degradation and encapsulated it within hollow manganese dioxide (HMnO2) nanoparticles, forming the lox@hmno2 composite. Additionally, they introduced a host-guest interacting macrocycle (pillar[5]arene, P[5]A) for capturing lipopolysaccharides (LPS), thereby reducing lactate production.

  • Synthesis and Modification: Using a silica template method, the researchers synthesized hollow nanoparticles and subsequently coated their surfaces with lactate oxidase and P[5]A-functionalized hyaluronic acid (HA) through a multi-step deposition process.

  • In Vitro Verification: The catalytic and capturing capabilities of lox@hmno2-p[5]a were tested via oxygen generation, lactate degradation, and LPS trapping experiments.

  • In Vivo Validation: A mouse model of LPS-induced sepsis was employed to study changes in lactate and LPS levels, as well as the recovery of organ function, to confirm the efficacy of the nanocomposite.

2. Unique Characteristics and Advanced Testing

  • Lactate Removal Functionality: The lox@hmno2 composite degrades lactate, producing hydrogen peroxide (H2O2), which is further catalytically converted into oxygen (O2) by HMnO2, forming a continuous catalytic cycle for lactate degradation. In a 20 mM lactate solution, lox@hmno2-p[5]a consumed up to 9 mM lactate within one hour.

  • LPS Capture Capability: Dynamic light scattering (DLS) and isothermal titration calorimetry (ITC) demonstrated that P[5]A interacts electrostatically with LPS to form a stable complex, effectively reducing lactate production in inflammatory conditions.

  • Endothelial Barrier Protection: In endothelial cell models, lox@hmno2-p[5]a significantly mitigated endothelial permeability by reducing lactate levels and stabilizing VE-cadherin expression.

Key Findings

  • Reductions in Circulating Lactate and LPS Levels: Intravenous administration of lox@hmno2-p[5]a reduced blood lactate levels by 52.2% and LPS levels by 65% within 48 hours in septic mice.

  • Suppression of Inflammatory Responses: Pro-inflammatory cytokines such as TNF-α and IL-6 were significantly downregulated, minimizing tissue damage and improving survival rates (100%).

  • Restoration of Multi-Organ Function: Histological analysis revealed reduced inflammatory cell infiltration and structural recovery in the organs of treated sepsis mice.

Significance and Highlights

Scientific Impact

This study advances our understanding of the underlying mechanisms of endothelial barrier dysfunction in sepsis, highlighting the critical role of lactate. Targeting lactate and its associated signaling pathways points to new directions in the treatment of other metabolic diseases, such as cancer.

Applications

The “dual-pipeline lactate removal strategy” represents a novel approach for mitigating inflammation in sepsis patients, offering potential for the development of high-efficiency and low-toxicity nanomedicines.

Technical Innovations

The introduction of P[5]A macrocycles and the cyclic catalytic system, leveraging H2O2-driven oxygen generation, underscores the innovation of this study in both nanomaterial design and biomedical application, showcasing the potential of interdisciplinary collaboration.

Conclusion

By leveraging a novel “dual-pipeline lactate removal strategy,” this research successfully demonstrated a nanomedicine-based solution for treating sepsis. It not only advances anti-inflammatory and endothelial protection therapies but also showcases the unique strengths of nanomedicine in addressing complex systemic illnesses. This breakthrough opens up new research directions in the treatment of sepsis and other metabolic disorders, offering a promising solution for pressing global health challenges.