PROJECT SUMMARY / ABSTRACT This proposal describes a concerted approach to the design, synthesis, and study of a novel reactive self- assembly approach, templated by proteins. In this approach, the templating proteins are incarcerated as guests into a matrix of host polymers. The resultant nanoassemblies are programmed to release these encapsulated proteins in their pristine form in the presence of a specific biologically-relevant stimulus or due to a combination of such stimuli. A key goal of the proposed research is to develop this into a new supramolecular platform that is useful for a broad range of soluble proteins, a capability that does not currently exist. The primary premise of the proposed research then is to develop a fundamental framework for custom- designing such supramolecular assemblies that can predictably encapsulate a protein, protect it from denaturation in non-native environments, and regain its native structure and function in response to a stimulus that is specific to the target environment. We will identify the structural factors that underlie the formation of these programmable molecular assemblies. We will develop this approach and evaluate its versatility through: (i) elucidation of the factors that control the self-assembly process such that the approach becomes broadly applicable to a wide-range of proteins;; (ii) incorporate responsive features in the assemblies for a range of specific intrinsic biological triggers, as well as specific combinations of such triggers;; and (iii) evaluation of strategies to traffic proteins across a cellular membrane to release them in specific intracellular compartments. The proposed research will result in a novel, polymeric supramolecular platform with implications in several unmet challenges in biomedicine.