Spatiotemporal delivery of endplate-targeted single-atom cerium nanozyme for immune-vascular crosstalk modulation and sclerosis attenuation.

Cartilage endplate (CEP) sclerosis is a critical pathological hallmark of intervertebral disc degeneration (IVDD) and a major contributor to low back pain, with reactive oxygen species (ROS) emerging as key upstream drivers of this process. Here, we report the design of a CEP-targeted cerium single-atom nanozyme (CAP@Ce SAs) that integrates ROS-scavenging capacity with tissue-specific targeting. CAP@Ce SAs exhibited robust superoxide dismutase- and catalase-like activities as well as hydroxyl radical elimination, while selective CEP enrichment was achieved via conjugation of the CEP-binding CAP peptide. In a lumbar spinal instability mouse model, CAP@Ce SAs effectively alleviated CEP degeneration and sclerosis, suppressed macrophage infiltration, and inhibited aberrant Type-H vessel angiogenesis. In vitro, CAP@Ce SAs protected chondrocytes from oxidative stress, and bulk RNA-seq combined with mechanistic validation demonstrated that the therapeutic effects are mediated by modulation of the ROS-Hippo-CCL5 axis. To our knowledge, this is the first CEP-targeted nanozyme that couples single-atom cerium catalysis with peptide-guided delivery, providing a precision strategy to remodel the immune-vascular microenvironment of CEP. These findings establish CAP@Ce SAs as a promising biomaterial platform for endplate-centered intervention in degenerative disc disease.