Spatiotemporally Programmable Adaptive Nanozyme Hydrogels with Ce Single-Atom/Cluster Heterostructures for Durable Multimodal Periodontitis Therapy

Abstract Periodontitis is a chronic inflammatory disease driven by dynamic microenvironmental imbalances, progressing through successive stages of bacterial infection, immune dysregulation, and tissue destruction. This complex microenvironment exhibits high spatiotemporal heterogeneity, rendering conventional therapies insufficient for stage-specific requirements. This work synthesizes nine-coordinated cerium atomic clusters alongside single atoms anchored on a nitrogen-doped carbon substrate (Ce ACSA@NC). Compared to conventional four-coordinated cerium single-atom structure (Ce SA@NC), Ce ACSA@NC possesses enhanced multi-enzyme mimetic activities, enabling spatiotemporally programed catalytic selectivity aligned with distinct pathological phases. Ce ACSA@NC performs multimodal cascade therapy: rapid antibacterial activity, sustained antioxidant activity, immune regulation, inhibition of bone resorption, and promotion of bone regeneration. Integrated with Pluronic F-127, an injectable thermosensitive hydrogel (Ce ACSA@NC/PF127) ensures precision and durability via staged intervention. This system rapidly eliminates bacteria and scavenges reactive oxygen species (ROS), disrupts the ROS-inflammatory feedback loop, reprograms macrophage polarization, suppresses pro-inflammatory cytokines while enhancing anti-inflammatory secretion, and coordinately modulates the NF-κB pathway and Nrf2 pathways. Through its intrinsic osteogenic properties, Ce ACSA@NC shields bone cells from inflammation, concurrently inhibiting resorption and fostering regeneration. Consequently, the Ce ACSA@NC/PF127 nanoplatform synergistically integrates antibacterial, antioxidant, anti-inflammatory, and osteogenic functions, offering a spatiotemporally adaptive strategy for precision periodontitis therapy with significant clinical potential.