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Double emulsion solvent evaporation is one of the most common techniques to formulate cytokines into vehicles made from hydrophobic polymers; however, the liquid\u2013liquid interfaces formed during emulsification can greatly affect the stability and therapeutic performance of encapsulated cytokines. To develop more effective cytokine\u2010delivery systems, a clear molecular understanding of the interactions between relevant proteins and solvents used in the preparation of such particles is needed. We utilized an integrated computational and experimental approach for studying the governing mechanisms by which interleukin\u201012 (IL\u201012), a clinically relevant cytokine, is protected from denaturation by albumin, a common stabilizing protein, at an organic\u2010aqueous solvent interface formed during double emulsification. We investigated protein\u2013protein interactions between human (h)IL\u201012 and albumin and simulated these components in pure water, dichloromethane (DCM), and along a water\/DCM interface to replicate the solvent regimes formed during double emulsification. We observed that (i) hIL\u201012 experiences increased structural deviations near the water\/DCM interface, and (ii) hIL\u201012 structural deviations are reduced in the presence of albumin. Experimentally, we found that hIL\u201012 bioactivity is retained when released from particles in which albumin is added to the aqueous phase in molar excess to hIL\u201012 and sufficient time is allowed for albumin\u2010hIL\u201012 binding. Findings from this work have implications in establishing design principles to enhance the stability of cytokines and other unstable proteins in particles formed by double emulsification for improved stability and therapeutic efficacy.<\/jats:p>","DOI":"10.1002\/btm2.10722","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T02:39:11Z","timestamp":1725590351000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Elucidating the role of carrier proteins in cytokine stabilization within double emulsion\u2010based polymeric nanoparticles"],"prefix":"10.1002","volume":"10","author":[{"given":"Emily R.","family":"Rhodes","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder  Boulder Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole 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