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The functional integration of these topics would open new avenues for treating diseases synergistically. However, these two individual topics have only been occasionally merged, probably because of the lack of functionalized design of macrocyclic host and the lack of efficient recognition between host and guest drugs. Herein, a \u201cdrug\u2010in\u2010drug\u201d strategy is proposed, in which an active drug is encapsulated by a macrocycle possessing therapeutic activity to form a multifunctional supramolecular active pharmaceutical ingredient. As a proof\u2010of\u2010concept, a complex of hydroxychloroquine (HCQ) with sulfonated azocalix[4]arene (HCQ@SAC4A) is prepared to treat rheumatoid arthritis (RA) in a combined fashion. SAC4A is a therapeutic agent that exhibits scavenging capacity for reactive oxygen species and exerts an anti\u2010inflammatory effect. It is also a hypoxia\u2010responsive carrier that can deliver HCQ directly to the inflammatory articular cavity. Consequently, HCQ@SAC4A achieves the synergistic anti\u2010inflammatory effect on both inflamed RAW 264.7 cells and RA rats. This effect is attributed to the temporal and spatial consistency of the two active ingredients of the complex. As a new paradigm for combinational therapy, the drug\u2010in\u2010drug strategy advances in easy preparation, mix\u2010and\u2010match combination, and precise ratiometric control.<\/jats:p>","DOI":"10.1002\/adma.202203765","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T23:23:37Z","timestamp":1654817017000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Drug in Drug: A Host\u2013Guest Formulation of Azocalixarene with Hydroxychloroquine for Synergistic Anti\u2010Inflammation"],"prefix":"10.1002","volume":"34","author":[{"given":"Shihui","family":"Li","sequence":"first","affiliation":[{"name":"College of Chemistry Key Laboratory of Functional Polymer Materials (Ministry of Education) State Key Laboratory of Elemento\u2010Organic Chemistry Nankai University  Tianjin 300071 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