Davoud Mozhdehi1
Syracuse University1
Recombinant nanoworms are promising candidates for materials and biomedical applications ranging from templated synthesis of nanomaterials to multivalent display of bioactive peptides and targeted delivery of theranostic agents. However, the molecular design principles to synthesize these assemblies (which are thermodynamically favorable only in a narrow region of the phase diagram) remains unclear. To advance the identification of design principles for programmable assembly of proteins into well-defined nanoworms and to broaden their stability regimes, we were inspired by well-documented findings of topological engineering for accessing rare mesophases formed by synthetic macromolecules. To test this design principle in biomacromolecular assemblies, we used posttranslational modifications (PTMs) to generate lipidated proteins with precise topological and compositional asymmetry. Using an integrated experimental and computational approach, we show that the material properties (thermoresponse and nanoscale assembly) of these hybrid amphiphiles are modulated by their amphiphilic architecture. Importantly, we demonstrate that the judicious choice of amphiphilic architecture can be used to program the assembly of proteins into adaptive nanoworms, that undergo a morphological transition (sphere-to-nanoworms) in response to temperature stimuli. Due to their amphiphilicity, these nanoworms can easily solubilize hydrophobic chemotherapeutics without resorting to complex, inefficient, and time-consuming conjugation/purification protocols. The recombinant nature of this system enables the fusion of genetically encoded bioactive or targeting peptides, which can be used to optimize the delivery and efficacy of these nanoplatforms. We anticipate that these methods will be generalizable to other classes of proteins and PTMs. Thus, this work advances the study and design other hybrid systems, such as proteins modified with other classes of lipids or charged PTMs such as phosphorylation.