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Oxidative stress is a crucial area of investigation among potential etiologies. We examined the hypothesis that blocking the angiotensin type 1 (AT1) receptor with valsartan (VST) in self-nanoemulsifying delivery systems (SNEDS) and loads in liquisolid tablets (LST-1) or valsartan and hydrochlorothiazide (VST\/HCTZ) in SNEDS and loads in liquisolid tablets (LST-2) in comparison with non-SNEDS liquisolid tablets (DCT-3 and DCT-4) would lead to an improvement in hypertension management. The present study aims to explore the molecular mechanisms underlying their effect in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. Male Sprague\u2013Dawley rats were given L-NAME (40\u00a0mg\/kg\/day) orally for three weeks to inhibit the endogenous synthesis of nitric oxide (NO). Concurrent treatment with VST or VST\/HCTZ liquisolid tablets (20\u00a0mg\/kg\/day for three weeks) resulted in lowering blood pressure (BP), reversing the L-NAME-induced serum NO suppression, enhancing lipid profile, and improving oxidative status. The antioxidant defense of paraoxonase was significantly increased in the LST-1- and LST-2-treated rats compared to the L-NAME-treated rats by 135% and 90%, respectively. Furthermore, SNEDS-loaded VST or SNEDS-loaded VST\/HCTZ liquisolid tablets significantly lowered the elevated level of AT1 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05), showed a marked Nrf2 expression (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01) and overexpressed PPAR\u03b3 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05), and suppressed iNOS expression (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.0001). These results highlight the remarkable benefits of the novel formula, \u201cSNEDS-loaded VST and SNEDS-loaded VST\/HCTZ,\u201d as an alternative therapy in treating hypertension and its complications.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical abstract<\/jats:bold>\n          <\/jats:p>\n          <jats:p>Schematic diagram showing the mechanism of SNEDS-loaded VST and SNEDS-loaded VST\/HCTZ as potential treatment strategies for hypertension. This mechanism includes the reduction of iNOS expression, antioxidant activity, and AT1R normalization action through activation of the Nrf2\/PPAR\u03b3 signaling cascade.<\/jats:p>","DOI":"10.1007\/s00210-025-03993-4","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T12:32:19Z","timestamp":1743251539000},"page":"12321-12341","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Nanoformulation of valsartan-loaded tablet attenuates L-NAME-induced hypertension: role of Nrf2\/PPAR\u03b3\/AT1 signaling pathway"],"prefix":"10.1007","volume":"398","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2585-9957","authenticated-orcid":false,"given":"Hanan","family":"Elimam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid M.","family":"El-Say","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarek A.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Marleau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zakaria","family":"El-Khayat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"El-Banna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihan","family":"Hussein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"3993_CR1","doi-asserted-by":"publisher","first-page":"9460653","DOI":"10.1155\/2017\/9460653","volume":"2017","author":"RF Abdel-Rahman","year":"2017","unstructured":"Abdel-Rahman RF et al (2017) Antihypertensive effects of roselle-olive combination in L-NAME-induced hypertensive rats. 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