Thermo-pH-Sensitive Polymer Conjugated Glucose Oxidase for Tumour-Selective Starvation-Oxidation-Immune Therapy.

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 tumour selectivity, and severe side effects, limit their wide applications in cancer therapy. Herein, we report screening of a thermo-pH-sensitive polymer-glucose oxidase conjugate that can controllably self-assemble into nanoparticles with improved stability. 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 tumour cell spheroid penetration of the conjugate are greatly enhanced under the acidic tumour microenvironment, leading to increased cytotoxicity to tumour cells. Upon a single intratumoural injection, the conjugate penetrates into the whole tumour tissue but hardly diffuses into the normal tissues, resulting in the eradication of the tumours in mice without perceivable side effects. Simultaneously, the conjugate induces a robust antitumour immunity to efficiently inhibit the growth of distant tumours, 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 tumour microenvironment for selective tumour therapy. This article is protected by copyright. All rights reserved.