{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T15:53:16Z","timestamp":1776873196834,"version":"3.51.2"},"reference-count":54,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Administration of Traditional Chinese Medicine Young Qihuang Scholar Project"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: The tumor microenvironment (TME) poses significant challenges to effective therapy, with cancer-associated fibroblasts (CAFs) playing a key role in tumor progression and drug resistance in triple-negative breast cancer (TNBC). Herein, a TME responsive nanocapsule, NPC-ABS\/FDS, was developed utilizing baicalein, a CAFs modulator, and the cytotoxic drug doxorubicin to selectively target CAFs and tumor cells, respectively, in a stepwise manner. Methods: NPC-ABS\/FDS was designed with CD13-mediated primary targeting for tumor accumulation and secondary targeting via \u03c3-receptor binding (ABS nanoparticles) for CAFs and folate modification (FDS nanoparticles) for cancer cells. Physicochemical properties were assessed using TEM, particle size, and \u03b6-potential analyses. Fluorescence imaging evaluated tumor retention, while cellular uptake and TME modulation were analyzed in vitro and in vivo. Results: The successful preparation of NPC-ABS\/FDS was demonstrated by its uniform morphology, stable characteristics, charge reversal, and increased particle size. Fluorescence imaging confirmed prolonged peritumoral retention. Cellular uptake increased 2.5-fold for baicalein in CAFs and 4.3-fold for doxorubicin in cancer cells. NPC-ABS\/FDS downregulated \u03b1-SMA and FAP, reducing CAFs activation, improving intratumoral drug penetration, and enhancing CD8+ and CD4+ T cell infiltration while decreasing regulatory T cells. Conclusions: NPC-ABS\/FDS effectively modulates multiple TME components, including CAFs and immune cells, and improves drug delivery in TNBC. These findings may support the development of improved therapeutic approaches for TNBC.<\/jats:p>","DOI":"10.3390\/pharmaceutics18020184","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T14:35:46Z","timestamp":1769783746000},"page":"184","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Taming the Tumor Stroma: A Two-Stage Targeted Nanocapsule for Potent Deep Chemo-Immunotherapy in Triple-Negative Breast Cancer"],"prefix":"10.3390","volume":"18","author":[{"given":"Bin","family":"Xing","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinru","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xintao","family":"Jia","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Haihe 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Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4449-6725","authenticated-orcid":false,"given":"Zhidong","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/s41571-021-00546-5","article-title":"Clinical and therapeutic relevance of cancer-associated fibroblasts","volume":"18","author":"Chen","year":"2021","journal-title":"Nat. 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