Biomimetic Multinuclear Nickel-Polyphenol Artificial Enzyme with Synergistic Catalytic Centers for Broad-Spectrum
Yuying Wang1, Ruifang Li2,3, Longwu Xu1
1Affiliated Hospital of Shandong Second Medical University, Shandong Second Medical University, Weifang 261053, Shandong, P. R. China.
Abstract:
Myocardial injury constitutes a life-threatening complication of sepsis, driven by synergistic oxidative-inflammatory pathology involving dysregulated production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and proinflammatory cytokines. This pathophysiological cascade remarkably elevates morbidity and mortality rates in septic patients, emerging as a key contributor to poor clinical outcomes. Despite its clinical significance, no clinically validated therapeutics currently exist for managing septic cardiomyopathy. Here, we present a novel nickel-salvianolic acid B metallopolymer (Ni-SalB) engineered through metal-coordination-driven self-assembly. This biohybrid therapeutic demonstrates multimodal catalytic efficacy in counteracting lipopolysaccharide (LPS)-induced myocardial injury through coordinated oxidative stress mitigation and inflammation regulation. The integration of catechol-carboxyl dual coordination centers with phenolic frameworks creates a synergistic system enhancing structural stability while enabling tandem catalytic cascade: (1) superoxide dismutase (SOD)-mimetic conversion of superoxide radicals (O2•-) to H2O2, followed by (2) glutathione peroxidase (GPx)-like decomposition of H2O2 to water. Mechanistic studies revealed the multifunctional scavenging capacity of Ni-SalB against diverse cytotoxic species, including hydroxyl radicals (•OH) and reactive nitrogen species(RNS), through electron transfer and radical recombination pathways. In murine sepsis models, Ni-SalB administration markedly attenuated myocardial oxidative damage, while enhancing endogenous antioxidant defenses. Histopathological analysis demonstrated therapeutic preservation of myocardial architecture, showing not only a great reduction in inflammatory infiltration but also a remarkably decrease in collagen deposition compared to septic controls. The catechol-carboxyl coordination architecture conferred enhanced pharmacokinetic properties with prolonged circulation life, while maintaining favorable biosafety profiles. This study introduces a metallo-polymeric artificial enzyme strategy with dual catalytic antioxidant systems, presenting a paradigm-shifting approach for managing sepsis-induced cardiac complications and expanding the translational promise of redox-modulation therapies.
Insights
A novel nickel-salvianolic acid B metallopolymer (Ni-SalB) effectively treats sepsis-induced myocardial injury by reducing oxidative stress and inflammation. This artificial enzyme enhances antioxidant defenses and preserves heart tissue, offering a promising therapeutic strategy for septic cardiomyopathy.
Area of Science:
- Biomaterials Science
- Cardiovascular Medicine
- Biochemistry
Background:
- Sepsis-induced myocardial injury is a severe complication driven by oxidative stress and inflammation, leading to high mortality.
- Current treatments for septic cardiomyopathy are limited, highlighting the need for novel therapeutic approaches.
- Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play critical roles in the pathophysiology of septic myocardial injury.
Purpose of the Study:
- To develop and evaluate a novel nickel-salvianolic acid B metallopolymer (Ni-SalB) as a therapeutic agent for sepsis-induced myocardial injury.
- To investigate the multimodal catalytic efficacy of Ni-SalB in mitigating oxidative stress and regulating inflammation in the heart.
- To assess the protective effects of Ni-SalB on myocardial architecture and function in preclinical sepsis models.
Main Methods:
- Metal-coordination-driven self-assembly was used to engineer the Ni-SalB metallopolymer.
- In vitro studies assessed the catalytic activities, including superoxide dismutase (SOD)-mimetic and glutathione peroxidase (GPx)-like functions, and scavenging of various cytotoxic species.
- In vivo studies utilized murine sepsis models (lipopolysaccharide-induced) to evaluate the therapeutic efficacy, pharmacokinetic properties, and biosafety of Ni-SalB.
Main Results:
- Ni-SalB demonstrated dual catalytic cascade activity, converting superoxide radicals to hydrogen peroxide and subsequently to water, while also scavenging hydroxyl radicals and RNS.
- Administration of Ni-SalB in murine sepsis models significantly attenuated myocardial oxidative damage and enhanced endogenous antioxidant defenses.
- Histopathological analysis revealed preserved myocardial architecture, reduced inflammatory infiltration, and decreased collagen deposition in Ni-SalB treated mice compared to controls.
- The Ni-SalB exhibited favorable pharmacokinetics with prolonged circulation and a good biosafety profile.
Conclusions:
- Ni-SalB represents a novel biohybrid therapeutic with potent antioxidant and anti-inflammatory properties for combating sepsis-induced myocardial injury.
- The metallo-polymeric artificial enzyme strategy with dual catalytic antioxidant systems offers a paradigm-shifting approach for managing septic cardiomyopathy.
- This study underscores the translational promise of redox-modulation therapies and metallo-polymeric artificial enzymes in treating critical cardiovascular complications of sepsis.
Related Concept Videos
01:26Heart Failure Drugs: Inotropic Agents
01:14Myocarditis III: Medical Management
01:30Cardiomyopathy II: Dilated Cardiomyopathy
01:29Cardiomyopathy V: Interprofessional Care