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The PI3K\/AKT\/mTOR pathway is highly activated in TNBC, making it a promising therapeutic target. Conventional PEGylated nanocarriers often face challenges, such as accelerated blood clearance and lysosomal trapping. To overcome these limitations, we developed a zwitterionic block copolymer, poly\u00ad(2-(N-oxide-dimethylamino)\u00adethyl methacrylate)-block-poly\u00ad(\u03b5-caprolactone) (OPDMA-PCL), via one-pot living anionic polymerization followed by postmodification. Compared with poly\u00ad(ethylene glycol)-block-poly\u00ad(\u03b5-caprolactone) (PEG-PCL) micelles, the OPDMA-PCL micelles exhibited prolonged systemic circulation, improved tumor targeting, and negligible immunogenicity. OPDMA-PCL micelles exhibited mitochondria-targeting properties in vitro. Loaded with gambogenic acid (GNA), OPDMA-PCL-GNA induces apoptosis in MDA-MB-231 cells by inhibiting the PI3K\/AKT\/mTOR pathway. In vivo, OPDMA-PCL-GNA achieved 91.2% tumor growth inhibition in xenograft models without systemic toxicity. This work establishes zwitterionic OPDMA-PCL micelles as a promising platform for TNBC therapy, overcoming key limitations of PEGylated systems while enabling organelle-specific drug delivery.<\/jats:p>","DOI":"10.1021\/acs.biomac.5c01461","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T13:08:38Z","timestamp":1757336918000},"page":"7125-7139","source":"Crossref","is-referenced-by-count":5,"title":["Mitochondrial-Targeting\nZwitterionic Nanomedicine\nBased on Tertiary Amine\n                    <i>N<\/i>\n                    \u2011oxide Polymers for\nTriple-Negative Breast Cancer Therapy"],"prefix":"10.1021","volume":"26","author":[{"given":"Yuxin","family":"Huang","sequence":"first","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenya","family":"Zhu","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Liu","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2595-8269","authenticated-orcid":true,"given":"Guowei","family":"Wang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0384-9213","authenticated-orcid":true,"given":"Wuli","family":"Yang","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 200433"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"issue":"3","key":"2026081812212084100_cit1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics\n2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for\n36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"Ca-Cancer J. 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