Modular Prodrug‐Engineered Oxygen Nano‐Tank With Outstanding Nanoassembly Performance, High Oxygen Loading, and Closed‐Loop Tumor Hypoxia Relief

Abstract The clinical translation of tumor hypoxia intervention modalities still falls short of expectation, restricted by poor biocompatibility of oxygen‐carrying materials, unsatisfactory oxygen loading performance, and abnormally high cellular oxygen consumption‐caused insufficient hypoxia relief. Herein, a carrier‐free oxygen nano‐tank based on modular fluorination prodrug design and co‐assembly nanotechnology is elaborately exploited, which is facilely fabricated through the molecular nanoassembly of a fluorinated prodrug (FSSP) of pyropheophorbide a (PPa) and an oxygen consumption inhibitor (atovaquone, ATO). The nano‐tank adeptly achieves sufficient oxygen enrichment while simultaneously suppressing oxygen consumption within tumors for complete tumor hypoxia alleviation. Significant, the fluorination module in FSSP not only confers favorable co‐assemblage of FSSP and ATO, but also empowers the nanoassembly to readily carry oxygen. As expected, it displays excellent oxygen carrying capacity, favorable pharmacokinetics, on‐demand laser‐triggerable ATO release, closed‐loop tumor hypoxia relief, and significant enhancement to PPa‐mediated PDT in vitro and in vivo. This study provides a novel nanotherapeutic paradigm for tumor hypoxia intervention‐enhanced cancer therapy.