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By exploiting FcRn-mediated recycling and enhanced thermodynamic stability, this strategy extends the circulatory half-life. Concurrently, interactions with Fc\u03b3Rs and complement component 1q (C1q) confer Fc-fusion proteins immunomodulatory functions, for example, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Recent clinical approvals of novel Fc-fusion biologics underscore the translational viability of Fc-fusion proteins. With ongoing innovations in artificial intelligence-guided design and engineered Fc scaffolds, Fc-fusion technology is positioned to dominate next-generation biotherapeutics. Notwithstanding advantages in pharmacokinetics, challenges such as target-mediated drug disposition (TMDD) and FcRn binding interference still need to be addressed. This study systematically evaluates the current status of Fc-fusion protein drugs and recent engineering advancements to enhance the application of Fc-fusion proteins in drug development.<\/jats:p>","DOI":"10.3389\/fphar.2026.1853458","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T04:21:26Z","timestamp":1784175686000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel biopharmaceutical strategies: Fc-fusion protein technology"],"prefix":"10.3389","volume":"17","author":[{"given":"Xin-Yuan","family":"Ding","sequence":"first","affiliation":[{"name":"Centre for Translational Medicine, Gansu Provincial Academic Institute for Medical Research","place":["Lanzhou, China"]},{"name":"Centre for Translational Medicine, Sun Yat-sen University Cancer Center Gansu Hospital","place":["Lanzhou, China"]},{"name":"MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Li","family":"Fan","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Miao","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Core Facility, School of Basic Medical Sciences, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Xiao","family":"Wei","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe-Zheng","family":"Lin","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai-Juan","family":"Bai","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital","place":["Lanzhou, China"]},{"name":"Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Hong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Centre for Translational Medicine, Gansu Provincial Academic Institute for Medical Research","place":["Lanzhou, China"]},{"name":"Centre for Translational Medicine, Sun Yat-sen University Cancer Center Gansu Hospital","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1002\/jcph.1545","article-title":"Concept of pharmacologic target\u2010mediated drug disposition in large\u2010molecule and small\u2010molecule compounds","volume":"60","author":"An","year":"2019","journal-title":"J. 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