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However, the intrinsically low blood\u2013brain\u2010barrier (BBB)\u2010crossing capability of PHT and upregulated expression level of the efflux transporter p\u2010glycoprotein (P\u2010gp) coded by the gene Abcb1 in epileptic neurons limit its efficacy in vivo. Herein, a nanointegrated strategy to overcome PHT resistance mechanisms for enhanced antiepileptic efficacy is reported. Specifically, PHT is first incorporated into calcium phosphate (CaP) nanoparticles through biomineralization, followed by the surface modification of the PEGylated BBB\u2010penetrating TAT peptide. The CaP@PHT\u2010PEG\u2010TAT nanoformulation could effectively cross the BBB to be taken in by epileptic neurons. Afterward, the acidic lysosomal environment would trigger their complete degradation to release Ca<jats:sup>2+<\/jats:sup> and PHT into the cytosol. Ca<jats:sup>2+<\/jats:sup> ions would inhibit mitochondrial oxidative phosphorylation to reverse cellular hypoxia to block hypoxia\u2010inducible factor\u20101\u03b1 (Hif1\u03b1)\u2010Abcb1\u2010axis, as well as disrupt adenosine triphosphate generation, leading to simultaneous suppression of the expression and drug efflux capacity of P\u2010gp to enhance PHT retention. This study offers an approach for effective therapeutic intervention against drug\u2010resistant epilepsy.<\/jats:p>","DOI":"10.1002\/smll.202300395","type":"journal-article","created":{"date-parts":[[2023,4,8]],"date-time":"2023-04-08T12:05:44Z","timestamp":1680955544000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Calcium Phosphate\u2010Based Nanoformulation Selectively Abolishes Phenytoin Resistance in Epileptic Neurons for Ceasing Seizures"],"prefix":"10.1002","volume":"19","author":[{"given":"Qiwen","family":"Guan","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University  Changsha 410008 China"},{"name":"Institute of Clinical Pharmacology and Engineering Research Center of Applied Technology of Pharmacogenomics of Ministry of Education Central South University  Changsha 410078 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science Chongqing University  Chongqing 400044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danfeng","family":"Cao","sequence":"additional","affiliation":[{"name":"Academician Workstation Changsha Medical University  Changsha 410219 China"},{"name":"The Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid Changsha Medical University  Changsha 410219 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menghuan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Science Chongqing University  Chongqing 400044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9019-3314","authenticated-orcid":false,"given":"Zhong","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Life Science Chongqing University  Chongqing 400044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5149-1204","authenticated-orcid":false,"given":"Xiaoyuan","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders Xiangya Hospital Central South University  Changsha 410008 China"},{"name":"Institute of Clinical Pharmacology and Engineering Research Center of Applied Technology of Pharmacogenomics of Ministry of Education Central South University  Changsha 410078 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,8]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.24"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1586\/ern.10.71"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2014-204670"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2003.10.012"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.041210"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2011.12.003"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.heliyon.2022.e09777","volume":"8","author":"Juvale I. 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