Hypoxia is a typical hallmark in several disease conditions, particularly in solid tumors. Thus, hypoxia-responsive nanocarriers that may specifically deliver and release payload under hypoxic conditions have been highly sought after, for precision medicine. Herein, we report the first hypoxia-responsive, covalently self-assembled polymer nanocapsules (NCs), formed via directly crosslinking perhydroxycucurbit[6]uril with a ditopic, hypoxia-responsive azobenzene derivative (AZO). Because of the presence of macrocyclic cucurbit[6]uril, the hypoxia-responsive nanocapsules (AZO-NCs) allowed modular, noncovalent surface functionalization. As a proof-of-concept, folate-functionalized AZO-NCs exhibited targeted payload delivery into cancer cells, and more importantly, hypoxia-responsive payload release was validated both in vitro and in vivo.