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Although hyaluronidase (HAase) can dismantle this barrier, systemic administration of HAase depletes HA from healthy tissues and causes dose\u2010limiting toxicities. Here we exploited the inherent hypoxia\u2010driven tumor\u2010homing capacity of\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    BL21 to create an autonomous, self\u2010amplifying delivery system (SHEc) that synthesized and secreted the highly active HA\u2010specific HAase (SHAase) from\n                    <jats:italic>Streptomyces koganeiensis<\/jats:italic>\n                    exclusively within the tumor. Guided by the pelB signal peptide, SHAase could be translocated to the periplasm and released into the extracellular space only where SHEc accumulates. In vitro, SHEc selectively colonized the necrotic core of HA\u2010rich multicellular tumor spheroids (MCTS) formed by Panc02 cells and TGF\u2010\u03b2\u2010activated NIH\/3T3 cancer\u2010associated fibroblasts, degrading 44.43% of HA within 24\u00a0h. This on\u2010site HA digestion increased drug penetration depth by 2.92\u2010fold, decreased hypoxic fraction by 54.81%, and enhanced gemcitabine\u2010induced apoptosis. Thus, SHEc converts a systemically toxic protein into a tumor\u2010restricted stromal remodeling agent, offering a safe and potent strategy to enhance chemotherapy against PDAC.\n                  <\/jats:p>","DOI":"10.1002\/mabi.70271","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:04:18Z","timestamp":1790805858000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineered Tumor\u2010Homing\n                    <i>Escherichia coli<\/i>\n                    for Localized Hyaluronic Acid Degradation and Stromal Remodeling in Pancreatic Cancer"],"prefix":"10.1002","volume":"26","author":[{"given":"Shuai","family":"Gao","sequence":"first","affiliation":[{"name":"Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering Jiangnan University  Wuxi People's Republic of China"},{"name":"School of Chemical 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