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Abstract Polymeric micro‐ and nanoparticles are useful vehicles for delivering cytokines to diseased tissues such as solid tumors. Double emulsion solvent evaporation is one of the most common techniques to formulate cytokines into vehicles made from hydrophobic polymers; however, the liquid–liquid interfaces formed during emulsification can greatly affect the stability and therapeutic performance of encapsulated cytokines. To develop more effective cytokine‐delivery 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‐12 (IL‐12), a clinically relevant cytokine, is protected from denaturation by albumin, a common stabilizing protein, at an organic‐aqueous solvent interface formed during double emulsification. We investigated protein–protein interactions between human (h)IL‐12 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‐12 experiences increased structural deviations near the water/DCM interface, and (ii) hIL‐12 structural deviations are reduced in the presence of albumin. Experimentally, we found that hIL‐12 bioactivity is retained when released from particles in which albumin is added to the aqueous phase in molar excess to hIL‐12 and sufficient time is allowed for albumin‐hIL‐12 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. 

Unaltered biological matter (biomatter) can be harnessed to fabricate cohesive, sustainable bioplastics. However, controlling the material properties of these bioplastics is challenging, as the contributions of different macromolecular building blocks to processability and performance are unknown. To deconvolute the roles of different classes of biomolecules, we developed experimental and computational methods to construct and analyze biomatter analogs composed of carbohydrates, proteins, and lipids. These analogs are intended to improve fundamental understanding of biomatter plastics. Spectroscopic analyses of biomatter analogs suggest that cohesion depends on protein aggregation during thermomechanical processing. Molecular dynamics simulations confirm that alterations to protein conformation and hydrogen bonding are likely the primary mechanisms underlying the formation of a cohesive, proteinaceous matrix. Simulations also corroborate experimental measurements highlighting the importance of hydrogen bonding and self-assembly between specific, small-molecule constituents. These conclusions may enable the engineering of next-generation biomatter plastics with improved performance.