Thermo‐pH‐Sensitive Polymer Conjugated Glucose Oxidase for Tumor‐Selective Starvation‐Oxidation‐Immune Therapy

Abstract Protein drugs are increasingly used as therapeutics for the treatment of cancer. However, their inherent drawbacks, such as poor stability, low cell membrane and tissue permeability, lack of tumor selectivity, and severe side effects, limit their wide applications in cancer therapy. Herein, screening of a thermo‐pH‐sensitive polymer–glucose oxidase conjugate that can controllably self‐assemble into nanoparticles with improved stability is reported. The size, surface charge, and bioactivity of the conjugate can be tuned by adjustment of the solution temperature and pH. The cellular uptake, intracellular hydrogen peroxide generation, and tumor cell spheroid penetration of the conjugate are greatly enhanced under the acidic tumor microenvironment, leading to increased cytotoxicity to tumor cells. Upon a single intratumoural injection, the conjugate penetrates into the whole tumor tissue but hardly diffuses into the normal tissues, resulting in the eradication of the tumors in mice without perceivable side effects. Simultaneously, the conjugate induces a robust antitumor immunity to efficiently inhibit the growth of distant tumors, especially in combination with an immune checkpoint inhibitor. These findings provide a novel and general strategy to make multifunctional protein‐polymer conjugates with responsiveness to the acidic tumor microenvironment for selective tumor therapy.