Biomimetic Multinuclear Nickel-Polyphenol Artificial Enzyme with Synergistic Catalytic Centers for Broad-Spectrum RONS Scavenging: A Therapeutic Strategy against LPS-Induced Septic Cardiomyopathy

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.