Precise Targeting One‐Carbon Metabolism for Potent Cancer Therapy and Metastasis Suppression

Abstract One‐carbon (1C) metabolism supports the de novo synthesis of purines and pyrimidines, which are essential for cancer growth. So far, the most employed assay for targeting 1C metabolism is using the inhibitors of specific enzymes. However, metabolic compensation undermines their efficacy, and the lack of cell selectivity limits their application. Herein, a bifunctional Pd nanocatalyst coated with the cancer cell membrane (Pd@M) has been constructed to target 1C metabolism in cancer cells, delivering precise and potent cancer therapy. On the one hand, the Pd@M can catalyze formate and cause its depletion to disrupt cytoplasmic 1C metabolism and suppress cell metastasis. On the other hand, the Pd@M activates prodrugs in situ by bioorthogonal catalysis to inhibit the compensatory pathway, which strongly decreases nucleotide synthesis flux, thus causing potent inhibition of cell proliferation. This work presents a new way to disrupt cytoplasmic 1C metabolism and suppress cell metastasis by combination of precise depletion of cancer cell formate and inhibition of the compensatory pathway by using bioorthogonal chemistry.