Dynamic Shielding of Arsenic‐loaded Transferrin with Calcium Manganese Carbonate Potentiates Antitumor Effects via Self‐enhanced Synergistic Therapy

Abstract Arsenic trioxide is a frontline drug for leukemia treatment; however, its successful application in solid tumors has not yet been fully achieved. Transferrin is an endogenous protein containing iron‐binding sites that can be used for loading arsenic for targeted delivery to solid tumors. However, the nonspecific expression of the transferrin receptor greatly limits transferrin‐based nanomedicines. Herein, the dynamic shielding of arsenic‐loaded transferrin with calcium manganese carbonate is proposed to potentiate strong antitumor effects via self‐enhanced synergistic therapy. The nanocloak enhances tumor accumulation and realizes responsive release in an acidic tumor microenvironment. The re‐exposed arsenic‐loaded transferrin penetrates deep into the tumor, binds specifically to the receptor, and exerts cytotoxicity via chemotherapy. Along with this process, the protein levels of NOX4, which is responsible for H 2 O 2 production, are upregulated. This biological effect facilitates self‐enhanced chemodynamic therapy and the co‐loaded glucose oxidase further ensures the initiation of this reaction. The released manganese ions catalyze the conversion of H 2 O 2 into hydroxyl radicals and effectively activate the cGAS‐STING signaling pathway for tumor inhibition. Collectively, these findings reveal the potent antitumor effects of the biomineralized nanomedicine and pave the way for translating arsenic into solid tumor therapy via targeted delivery and synergistic therapy.