Ultrasmall Cerium-EGCG Nanoparticles Ameliorate Sepsis via Macrophage Reprogramming and Ferroptosis Inhibition

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, in which oxidative stress, ferroptosis, and macrophage-driven immune dysregulation form a self-amplifying pathological cycle. Epigallocatechin gallate (EGCG), a natural polyphenol with antioxidant and immunomodulatory activities, holds therapeutic potential for sepsis but is limited by rapid metabolism and low bioavailability. To overcome these limitations, we constructed ultrasmall Ce-EGCG nanoparticles (NPs) via one-pot metal-phenolic coordination self-assembly between cerium ions and EGCG. The resulting NPs exhibited excellent colloidal stability and efficient cellular internalization. Ce-EGCG NPs displayed dual catalase- and superoxide-dismutase-mimetic activities, scavenging both cytosolic and mitochondrial reactive oxygen species, and consistently outperformed equivalent doses of free EGCG and free Ce ions, demonstrating that the assembled metal-phenolic architecture is essential for the observed activity. In LPS- or H2O2-stimulated macrophages, Ce-EGCG NPs reversed Fe2+ overload, suppressed lipid peroxidation, and reprogrammed macrophages from a pro-inflammatory M1 toward an anti-inflammatory M2 phenotype. In CLP-induced septic mice, Ce-EGCG NPs ameliorated multi-organ injury, attenuated systemic cytokine storm, and improved survival, while showing favorable biosafety. Mechanistically, Ce-EGCG NPs activate the Nrf2/HO-1/NQO1 antioxidant axis and the GPX4/SLC7A11/ACSL4 anti-ferroptotic axis. Together, these findings show that Ce-EGCG NPs break the oxidative-ferroptotic-inflammatory cycle of sepsis through coordinated antioxidant, anti-ferroptotic, and immunomodulatory actions, offering a rationally designed nanotherapeutic strategy for sepsis and related inflammatory conditions.