Hypoxia-responsive polyphenol prodrug for targeted glucose oxidase delivery and enhanced multimodal cancer therapy

Hypoxia within tumor microenvironments significantly hinders the effectiveness of cancer therapies, particularly when using glucose oxidase (GOx) due to its exacerbation of hypoxic condition, leading to suboptimal therapeutic outcomes. To overcome this challenge, we developed a novel hypoxia-responsive galloylated prodrug to synergistically deliver GOx, leveraging the high affinity of polyphenols with proteins. The resulting nanocomplexes, created through a nanoprecipitation technique, demonstrated excellent colloidal stability, and were capable of killing tumor cells through multiple pathways: glucose consumption for starvation therapy, reactive oxygen species (ROS) generation to disturb redox homeostasis, and aggravated hypoxia-driven self-strengthened chemotherapy. In vitro and in vivo experiments confirmed that the engineered nanocomplexes not only extended circulation time and improved tumor accumulation, but also significantly intensified tumor hypoxia, facilitating prodrug activation. This approach yielded optimal therapeutic efficacy with minimal toxicity, offering a promising strategy for the delivery of protein biologics in cancer treatment.