Stimulus-responsive hydrogels based on host-guest interactions have attractive tremendous attentions in recent years, and have been applied successfully in a variety of research areas. Currently, a lot of macrocyclic hosts-such as cyclodextrin, crown ether, calixarenes, cucurbiturils, and pillararenes, etc. -have been widely investigated in the preparation of stimulus-responsive supramolecular hydrogels. The major approach to introduce stimulus-responsive properties into these supramolecular hydrogels is exploiting specially designed guests which can response to external stimuli. However, most of functional guests-such as organic dyes-are fail to manifest stimulus-responsive properties, which is a big limitation for the development of functional host-guest supramolecular hydrogels. Introducing stimulus-responsive hosts with excellent guest-binding abilities as the building blocks of supramolecular hydrogels may be an efficient way to address this problem. Herein, hyaluronic acid (HA) was modified with N-ethylamino-4-azetidinyl-1,8-naphthalene anhydride (EANA) dyes and used as the polymeric backbone of the hydrogel, and a hypoxia-responsive, deep-cavity azocalix[4]arene (CSAC4A) was exploited as the noncovalent cross-linking agent. By utilizing the strong 1: 2 recognition interactions between CSAC4A and the EANA moieties on the HA backbones, a new supramolecular hydrogel with hypoxiaresponsiveness was prepared, and its morphology, mechanical properties, and hypoxia-responsive behavior were fully characterized. It has been showed that, the pore sizes of HA-CA are mainly distributed in the range of 40-70 mu m, which indicates HA-CA is a typical microporous supramolecular hydrogel. Besides, the storage modulus (G') of HA-CA is stable at around 100 Pa, under the evaluation conditions of 0.5% strain, 1 Hz. When HA-CA was put under a hypoxia environment, the azo bonds of CSAC4A were reduced and cleaved, leading to the release of the encapsulated EANA dyes along with the recovery of their fluorescent emission. At the same time, due to the destruction of the physical cross-linking points, the cross-linked structure of the supramolecular hydrogel was destroyed, and its mechanical strength was significantly reduced. Therefore, HA-CA represents a novel type of hypoxia-responsive supramolecular hydrogel which might be potentially useful for biomedical applications.