Reprogramming Sphingolipid Metabolic and Redox Homeostasis with an Injectable Botanicals/Nanozymes Hydrogel for Inhibiting Postoperative Recurrence and Metastasis in Breast Cancer

Abstract

ABSTRACT Postoperative recurrence and metastasis in breast cancer remain major clinical challenges, primarily driven by persistent inflammation responses and secondary infections at surgical sites. These pathological processes trigger sphingolipid dysregulation and generate the redox imbalance for sustaining a chronic inflammation‐metabolism feedback loop and promoting tumor regeneration. However, current therapeutic modalities frequently exhibit insufficient capacity to concomitantly attenuate inflammatory cascades, scavenge reactive oxygen species (ROS), and restore metabolic homeostasis. Herein, we developed a multifunctional injectable botanicals/nanozyme hydrogel (CGHD) that restores redox balance and reprograms sphingolipid metabolism to inhibit tumor relapse. Under near‐infrared irradiation, CGHD triggered cascade catalytic reactions that scavenged ROS and downregulated sphingosine and sphingosine kinase‐1, thereby disrupting the inflammation–metabolism feedback loop driving tumor regeneration. In postoperative breast cancer models, CGHD accelerated wound healing and significantly suppressed recurrence and metastasis of residual tumors. Multi‐omics analyses further showed that CGHD alleviated oxidative stress, remodeled sphingolipid metabolism, and suppressed NF‐κB and TNF signaling. These effects decreased IL‐6 and TNF‐α expression while increasing IL‐10 levels. Collectively, these findings identify sphingolipid metabolism as a therapeutic target linking oxidative stress, inflammation, and postoperative tumor progression, highlighting CGHD as a promising strategy for recurrence prevention.