Polyphenol‐based nanomedicines (ESND) synthesized via the Mannich condensation of selenomethionine and epigallocatechin gallate effectively reduce abnormal Fe2+ accumulation, GPX4 inactivation, and lipid peroxidation in chondrocytes, ameliorating ferroptosis‐induced metabolic disorders in chondrocytes. This evidence concerns the gene GPX4 and metabolic disease.