Retooling Cancer Nanotherapeutics' Entry into Tumors to Alleviate Tumoral Hypoxia

Anti-hypoxia cancer nanomedicine (AHCN) holds exciting potential in improving oxygen-dependent therapeutic efficiencies of malignant tumors. However, most studies regarding AHCN focus on optimizing structure and function of nanomaterials with presupposed successful entry into tumor cells. From such a traditional perspective, the main barrier that AHCN needs to overcome is mainly the tumor cell membrane. However, such an oversimplified perspective would neglect that real tumors have many biological, physiological, physical, and chemical defenses preventing the current state-of-the-art AHCNs from even reaching the targeted tumor cells. Fortunately, in recent years, some studies are beginning to intentionally focus on overcoming physiological barriers to alleviate hypoxia. In this Review, the limitations behind the traditional AHCN delivery mindset are addressed and the key barriers that need to be surmounted before delivery to cancer cells and some good ways to improve cell membrane attachment, internalization, and intracellular retention are summarized. It is aimed to contribute to Review literature on this emerging topic through refreshing perspectives based on this work and what is also learnt from others. This Review would therefore assist AHCNs researchers to have a quick overview of the essential information and glean thought-provoking ideas to advance this sub-field in cancer nanomedicine.