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This study leverages the synergistic potential of curcumin (CUR) and berberine (BBR) co\u2010crystals encapsulated in a nanohydrogel to address these challenges through a pharmacokinetically and pharmacodynamically targeted therapeutic strategy. The nanohydrogel formulation significantly improves the solubility, stability, and bioavailability of CUR\/BBR co\u2010crystals, optimizing their therapeutic delivery and sustained release under physiological and tumor microenvironment conditions. On the other hand, the dual inhibitory mechanism of CUR and BBR, with CUR covalently binding to the active site of caspase\u20103 and BBR non\u2010covalently targeting the allosteric site, achieves enhanced apoptotic activity by disrupting both the catalytic and conformational functions of caspase\u20103. In\u00a0vitro cytotoxicity assays demonstrate remarkable efficacy of the CUR\/BBR nanohydrogel, achieving an IC50 of 12.36\u2009\u03bcg\/mL against HEC\u201059 endometrial cancer cells, significantly outperforming the individual components and the standard drug Camptothecin (IC50: 17.27\u2009\u03bcg\/mL). Caspase\u20103\/7 assays confirm enhanced apoptosis induction for the nanohydrogel formulation compared to co\u2010crystals alone and Camptothecin. Molecular dynamics simulations and binding free energy analyses further validate the synergistic interaction of CUR and BBR in their dual binding mode. This study introduces a novel therapeutic approach by enhancing drug delivery and dual targeting mechanisms, demonstrating the potential of CUR\u2010BBR nanohydrogel as a robust therapy for EC. This strategy offers a promising platform for addressing drug resistance and improving outcomes in endometrial cancer therapy.<\/jats:p>","DOI":"10.1002\/jmr.70004","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T01:05:55Z","timestamp":1742259955000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Nanohydrogel of Curcumin\/Berberine Co\u2010Crystals Induces Apoptosis via Dual Covalent\/Noncovalent Inhibition of Caspases in Endometrial Cancer Cell Lines: The Synergy Between Pharmacokinetics and Pharmacodynamics"],"prefix":"10.1002","volume":"38","author":[{"given":"Feiyan","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Gynecology, The Second Affiliated Hospital of Xi'an Medical University  Xi\u2019an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gynecology, The Second Affiliated Hospital of Xi'an Medical University  Xi\u2019an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gynecology, The Second Affiliated Hospital of Xi'an Medical University  Xi\u2019an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Gynecology, The Second Affiliated Hospital of Xi'an Medical University  Xi\u2019an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernest","family":"Oduro\u2010Kwateng","sequence":"additional","affiliation":[{"name":"Molecular Bio\u2010Computation and Drug Design Research Group, School of Health Sciences University of KwaZulu Natal, Westville Campus  Durban South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8711-7783","authenticated-orcid":false,"given":"Mahmoud E. 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