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Mutant PA (mPA) was recently fused to epidermal growth factor (EGF) to retarget delivery of LF<jats:sub>N<\/jats:sub> to cells bearing EGF receptors (EGFR), but the requirement for a known cognate ligand limits the applicability of this approach. Here, we render practical protective antigen retargeting to a variety of receptors with mPA single\u2010chain variable fragment (scFv) fusion constructs. Our design enables the targeting of two pancreatic cancer\u2010relevant receptors, EGFR and carcinoembryonic antigen. We demonstrate that fusion to scFvs does not disturb the basic functions of mPA. Moreover, mPA\u2212scFv fusions enable cell\u2010specific delivery of diphtheria toxin catalytic domain and Ras\/Rap1\u2010specific endopeptidase to pancreatic cancer cells. Importantly, mPA\u2212scFv fusion\u2010based treatments display potent cell\u2010specific toxicity in\u2005vitro, opening fundamentally new routes toward engineered immunotoxins and providing a potential solution to the challenge of targeted protein delivery to the cytosol of cancer cells.<\/jats:p>","DOI":"10.1002\/cbic.202000201","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T12:41:35Z","timestamp":1588682495000},"page":"2772-2776","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Anthrax Protective Antigen Retargeted with Single\u2010Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells"],"prefix":"10.1002","volume":"21","author":[{"given":"Alexander R.","family":"Loftis","sequence":"first","affiliation":[{"name":"Department of Chemistry Massachusetts Institute of Technology  77 Massachusetts Avenue Cambridge MA 02139 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael S.","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Massachusetts Institute of Technology  77 Massachusetts Avenue Cambridge MA 02139 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas L.","family":"Truex","sequence":"additional","affiliation":[{"name":"Department of Chemistry Massachusetts Institute of Technology  77 Massachusetts Avenue Cambridge MA 02139 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Biancucci","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology Feinberg School of Medicine Northwestern University  420 E Superior Street Chicago IL 60611 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karla J. 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