{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T09:48:05Z","timestamp":1761731285915,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T00:00:00Z","timestamp":1761350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation (DFG) CRC 1279","award":["316249678"],"award-info":[{"award-number":["316249678"]}]},{"name":"CRC 1149","award":["251293561"],"award-info":[{"award-number":["251293561"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JFB"],"abstract":"<jats:p>Metastatic breast carcinoma (BC) cells are prone to spreading in the bone microenvironment, leading to a vicious cycle between local osteoclast-mediated osteolysis and tumor progression. Therefore, the targeted pharmacological down-modulation of BC cell proliferation as well as osteoclast differentiation and hyperactivity might represent a promising treatment option. We developed a multifunctional peptide nanocarrier combining bioactive EPI-X4 peptides and the Rho-inhibiting C3bot enzyme from Clostridium botulinum. C3bot is preferentially internalized into the cytosol of monocytic cells, including osteoclasts, where it inhibits Rho-mediated signal transduction. However, Rho-mediated cellular processes like migration and cell division can also be inhibited in non-monocytic cells if C3bot is delivered into their cytosol by a nanocarrier. To accomplish this, we designed a supramolecular transporter where one molecule of biotinylated C3bot and three biotinylated entities of the human EPI-X4 peptide-derived CXCR4 antagonist JM173 are assembled on avidin as a central platform. This modular transport system (JM173)3-Avi-C3 down-modulated osteoclast formation and hyperactivity and delivered the therapeutic cargo C3bot successfully into the cytosol of breast cancer cells, where it inhibited Rho.<\/jats:p>","DOI":"10.3390\/jfb16110399","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T02:23:28Z","timestamp":1761704608000},"page":"399","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multifunctional Peptide-Based Biohybrid for Targeted Reduction of Metastatic Breast Carcinoma-Associated Osteolysis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8997-866X","authenticated-orcid":false,"given":"Nicole","family":"Stadler","sequence":"first","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingjie","family":"Gao","sequence":"additional","affiliation":[{"name":"Max-Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Jose","family":"Silva","sequence":"additional","affiliation":[{"name":"Max-Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6498-3649","authenticated-orcid":false,"given":"Joscha","family":"Borho","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Haunschild","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaloian","family":"Koynov","sequence":"additional","affiliation":[{"name":"Max-Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3333-2613","authenticated-orcid":false,"given":"Melanie","family":"Haffner-Luntzer","sequence":"additional","affiliation":[{"name":"Institute of Orthopaedic Research and Biomechanics, Centre of Musculoskeletal Research, Ulm University Medical Center, Helmholtzstra\u00dfe 14, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4782-1979","authenticated-orcid":false,"given":"Anita","family":"Ignatius","sequence":"additional","affiliation":[{"name":"Institute of Orthopaedic Research and Biomechanics, Centre of Musculoskeletal Research, Ulm University Medical Center, Helmholtzstra\u00dfe 14, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3599-6760","authenticated-orcid":false,"given":"Gilbert","family":"Weidinger","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3945-4491","authenticated-orcid":false,"given":"Seah Ling","family":"Kuan","sequence":"additional","affiliation":[{"name":"Max-Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5906-7205","authenticated-orcid":false,"given":"Tanja","family":"Weil","sequence":"additional","affiliation":[{"name":"Max-Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holger","family":"Barth","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,25]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2025, August 20). 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