Modulating Bioactive Moieties on Self‐Assembled Poly‐Curcumin Nanoparticles via Electrochemical Tuning to Attenuate Inflammation in Sepsis

Sepsis is a life-threatening syndrome driven by dysregulated inflammation that leads to tissue injury, multi-organ failure, and high mortality, despite advances in supportive care. Here, a nanotherapeutic approach is reported using self-assembled poly-curcumin nanoparticles (PCur-SANPs) formed by alkali-catalyzed polymerization and then fine-tuned by electrochemical modulation to enrich bioactive surface moieties. Time-resolved ¹H NMR and LDI-TOF MS show the formation and controlled evolution of phenolic derivatives, including phenol, cinnamyl alcohol, gentisyl alcohol, and vanillic acid, which correlate with maximal antioxidant capacity and cytokine suppression at an optimized treatment window (PCur-SANPs₃₀). In lipopolysaccharide (LPS)-stimulated models, PCur-SANPs₃₀ reduced TNF-α and IL-6 by more than 60% and inhibited nuclear factor kappa B (NF-κB) p65 nuclear translocation, indicating pathway-level modulation of the inflammatory response. In vivo, PCur-SANPs₃₀ alleviated clinical symptoms, preserved organ function, and improved survival to ≈80-85% in an LPS-induced sepsis model, outperforming free curcumin. This work establishes a simple, mechanism-guided electrochemical strategy for interfacial editing of nature-derived nanomaterials, transforming curcumin into a stable, bioactive platform. The demonstrated reduction of systemic inflammation and the survival benefit position PCur-SANPs as promising candidates for sepsis therapy and other inflammation-driven disorders.