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Among emerging therapeutic approaches, ferroptosis induction has attracted increasing attention due to its unique mode of action; however, its efficacy is often restricted by insufficient intratumoral drug accumulation and the abnormal tumor vascular microenvironment. Here, we designed a CREKA-modified peptide, Pep1, to actively target tumor-associated fibrin and increase accumulation in the tumor and further developed a pH-responsive self-assembling nanoplatform, PS\/Pep1. PS\/Pep1 significantly improved intratumoral drug bioavailability, promoted lipid peroxidation, suppressed glutathione peroxidase 4 (GPX4) activity, and downregulated vascular endothelial growth factor (VEGF) expression, thereby inducing ferroptosis- and apoptosis-mediated tumor cell death while suppressing angiogenesis. Upon exposure to the acidic tumor microenvironment, PS\/Pep1 transformed from spherical nanoparticles into aggregates with high aspect ratios, facilitating deep tumor penetration and sustained local retention. In summary, this study presents a smart nanomedicine strategy that integrates active targeting, microenvironment-responsive structural transformation, and the synergistic regulation of ferroptosis-mediated cell death and angiogenesis, providing a promising therapeutic paradigm for TNBC treatment.<\/jats:p>","DOI":"10.1021\/acsbiomaterials.6c00577","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T07:12:23Z","timestamp":1783062743000},"page":"4265-4277","source":"Crossref","is-referenced-by-count":1,"title":["A Microenvironment-Driven Peptide Nanoplatform Enhances Ferroptosis and Antiangiogenic Activity for Triple-Negative Breast Cancer Therapy"],"prefix":"10.1021","volume":"12","author":[{"given":"Yuanyuan","family":"Chen","sequence":"first","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumei","family":"Sun","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Li","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Chen","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziru","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fantao","family":"Lin","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanxin","family":"Song","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Li","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongying","family":"Gong","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohe","family":"Xiao","sequence":"additional","affiliation":[{"name":"The Fifth Medical Center of Chinese PLA General Hospital , , ,","place":["Beijing, China, 100039"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changgang","family":"Sun","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9749-2213","authenticated-orcid":true,"given":"Jingkun","family":"Bai","sequence":"additional","affiliation":[{"name":"Shandong Second Medical University , , ,","place":["Weifang, China, 261053"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"issue":"1","key":"2026081717142751100_cit1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-022-01260-0","article-title":"Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies","volume":"15","author":"Liao","year":"2022","journal-title":"J. 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