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Effective inhibition of P\u2010gp transport is important for high efficacy of chemotherapeutic drugs. Herein, a smart platform (CaO\n                    <jats:sub>2<\/jats:sub>\n                    @HA\u2010CAT\u2010DOX\u2010FA) is proposed to reduce the expression of P\u2010gp through the combination of hypoxia alleviation and adenosine triphosphate (ATP) suppression, thereby effective diminishing the efflux of chemotherapeutic drug. Hyaluronic acid (HA) can protect calcium peroxide (CaO\n                    <jats:sub>2<\/jats:sub>\n                    ) from premature depletion. The nanocomposite is further conjugated with folic acid (FA) to endow it with tumor\u2010targeting ability. At the tumor site, the nanocomposite disintegrates and releases calcium ion (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ), doxorubicin (DOX), catalase (CAT), and coincidentally produces a large amount of hydrogen peroxide (H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    ) in the acidic tumor microenvironment\u00a0(TME) containing hyaluronidase.\u00a0Subsequently, CAT can catalyze the transformation of H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    into oxygen (O\n                    <jats:sub>2<\/jats:sub>\n                    ) ameliorating the hypoxia. Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010overloading\u2010induced mitochondrial dysfunction can interrupt ATP synthesis and restrain cellular respiration decreasing O\n                    <jats:sub>2<\/jats:sub>\n                    consumption. With the combination of relieving hypoxia and suppressing ATP production, the expression of P\u2010gp was remarkable downregulated, thereby overcoming MDR, with confirmed by in\u2005vitro and in\u2005vivo experiments. This study may provide new avenues for the treatment of multidrug\u2010resistant tumors.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202505701","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T05:58:49Z","timestamp":1768543129000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reversing Multidrug Resistance via Efficient Inhibition of Drug Efflux for Enhanced Cancer Therapy"],"prefix":"10.1002","volume":"15","author":[{"given":"Xinhe","family":"Liu","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering, Henan Normal University  Xinxiang China"},{"name":"Henan International Joint Laboratory of Smart Molecules and Identification and Diagnostic Functions Henan Normal University  Xinxiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunchuan","family":"Tian","sequence":"additional","affiliation":[{"name":"School 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