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In this study, we synthesized poly(\u03b5\u2010caprolactone)\u2010<jats:italic>co<\/jats:italic>\u2010poly(ethylene glycol) (PCL\u2010<jats:italic>co<\/jats:italic>\u2010PEG) and fabricated LTZ\u2010loaded PCL\u2010<jats:italic>co<\/jats:italic>\u2010PEG NPs (LTZ\u2010NPs) via emulsion\u2010solvent evaporation. Folic acid (FA), a folate receptor\u2010targeting molecule, was conjugated to the LTZ\u2010loaded NPs (LTZ\u2010FNPs) to enhance treatment efficacy against hormone receptor\u2010positive breast cancer cells. Both NPs and FNPs exhibited a spherical morphology (60\u201390 nm), with FNPs showing higher drug entrapment efficiency and controlled release. LTZ release was minimal at physiological pH but increased in acidic, cancer\u2010like environments, following the Korsmeyer\u2010Peppas model, indicating a combination of Fickian and non\u2010Fickian diffusion. In cytotoxicity assays, LTZ\u2010FNPs exhibited higher toxicity against MCF\u20107 cells than LTZ\u2010NPs. Controlled LTZ release altered gene expression, reducing B\u2010cell leukemia\/lymphoma 2 protein (Bcl2) and increasing caspase 8 (Casp8), promoting apoptosis. A shift to the SubG1 phase further confirmed enhanced LTZ\u2010FNP\u2010mediated cell death. Furthermore, p53 expression increased, while matrix metalloproteinase 9 (MMP\u20109) decreased, inhibiting cell invasion. This study introduces a biodegradable system with FA\u2010functionalized, pH\u2010sensitive NPs for the targeted and controlled delivery of LTZ. This approach holds great potential for selective, efficient treatment while minimizing systemic toxicity in breast cancer therapy.<\/jats:p>","DOI":"10.1002\/mabi.202400558","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T10:16:56Z","timestamp":1744971416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Engineering Folic Acid\u2010Modified Nanoparticles to Enhance Letrozole's Anticancer Action"],"prefix":"10.1002","volume":"25","author":[{"given":"Neda","family":"Rostami","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering Arak University  Arak 3848177584 Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abuzar","family":"Nikzad","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology Rutgers University  Piscataway NJ 08854 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shervin","family":"Shaybani","sequence":"additional","affiliation":[{"name":"Department of Chemistry Wake Forest University  Winston\u2010Salem NC 27101 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hadi","family":"Noei","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Genetics Faculty of Medicine Istinye University  Istanbul 34010 Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aida","family":"Ghebleh","sequence":"additional","affiliation":[{"name":"School of Advanced Technologies in Medicine Isfahan University of Medical Sciences  Isfahan 8174673461 Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehdi","family":"Alidadi","sequence":"additional","affiliation":[{"name":"Department of Anatomy School of Medicine Tehran University of Medical Sciences  Tehran 1461884513 Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanie","family":"Abbasi","sequence":"additional","affiliation":[{"name":"Department of Medicine School of Medicine Tehran University of Medical Sciences  Tehran 1461884513 Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7704-5608","authenticated-orcid":false,"given":"Sidi A.","family":"Bencherif","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Northeastern University  Boston MA 02115 USA"},{"name":"Polymers, Biopolymers Surfaces Laboratory (PBS, UMR CNRS 6270) University of Rouen Normandy  Rouen F\u201076000 France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,4,18]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0111-2"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/smsc.202400192"},{"key":"e_1_2_10_3_1","first-page":"6","volume":"12","author":"Hanna K.","year":"2021","journal-title":"J. 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