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Existing formulations only partially overcome these limitations and often lack tumor-microenvironment\u2013responsive release or a clear understanding of how carrier composition modulates biological outcomes. Here, chitosan-coated zinc ferrite (ZFO@CS) and manganese ferrite (MFO@CS) nanocarriers were developed as pH- and glutathione-responsive platforms for capsaicin delivery. The nanocarriers exhibited nanoscale hydrodynamic diameters (~\u2009120\u2013500\u00a0nm) and highly positive zeta potentials (+\u200930 to +\u200950 mV), enabling high encapsulation efficiencies (up to ~\u200988%) and colloidal stability. Under physiological pH 7.4, less than 10% of the loaded drug was released over 48\u00a0h, whereas ~\u200930\u201340% was liberated under acidic, glutathione-rich conditions mimicking the tumor microenvironment, indicating dual stimulus-triggered behavior. Encapsulation improved capsaicin\u2019s selective cytotoxicity toward HepG2 liver cancer cells, with CAP-MFO@CS achieving a higher therapeutic index than free capsaicin, while maintaining acceptable compatibility with normal WI-38 fibroblasts. The nanocarriers also enhanced antibacterial and antioxidant activities. DNA binding and stopped-flow kinetics revealed that ferrite core composition modulates binding affinity and kinetic stability of DNA\u2013nanocomposite complexes, providing a mechanistic link between material properties and bioactivity. These findings demonstrate that core-dependent design of ferrite\u2013chitosan nanocarriers can improve capsaicin bioavailability, selectivity, and multifunctional therapeutic performance.<\/jats:p>","DOI":"10.1038\/s41598-026-40433-6","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T06:21:15Z","timestamp":1773382875000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Stimuli-responsive chitosan-coated ferrite nanocarriers for targeted capsaicin delivery and core-dependent HepG2-selective bioactivity"],"prefix":"10.1038","volume":"16","author":[{"given":"Eman","family":"Bakr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fawzya I.","family":"Elshami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehab A.","family":"Okba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanaa","family":"Mansour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaban Y.","family":"Shaban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"40433_CR1","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s12951-018-0392-8","volume":"16","author":"JK Patra","year":"2018","unstructured":"Patra, J. 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