Design Strategies of Hypoxia-Responsive Nanocarriers for Targeted Drug Delivery in the Tumor Microenvironment

Hypoxia is one of the hallmark features of solid tumors, and it leads to treatment resistance, metastasis, and immunosuppression. While physiological hypoxic microenvironments also exist in normal tissues, tumor hypoxia has more severe, longer-lasting, and higher spatial heterogeneity pathological characteristics. This important feature makes it an attractive trigger for nanomedicine drug delivery systems, and hypoxia-responsive nanocarriers are being developed as a preclinical strategy to utilize this property for the controlled release of drugs at specific spatiotemporal locations. This review focuses on four dimensions: hypoxia-responsive chemical groups and their nano-carriers, hypoxia-activated prodrugs, oxygen supply and oxygen-generating systems, and multi-stimuli integration, which mainly explores design strategies and representative cases of hypoxia-responsive nanocarriers for drug delivery, comparing their mechanisms, advantages, and limitations. The core conclusion is that the rational design of hypoxia-responsive nanocarriers should match the pathological characteristics of hypoxia in the tumor microenvironment, while being supplemented by multi-stimulus integration and dynamic penetration strategies. Key design principles and current transformation challenges were summarized in the end, aimed to provide guidance for the future design and application of hypoxia-targeted nanomedicines.