Project Summary/Abstract The merger of synthetic polymers and biological systems has a significant history, but many of the materials chosen for targeted applications are selected due to their commercial availability or ease of access. These materials rarely elicit all of the features that would be desirable such as degradability, biocompatibility, and control over polymer architecture and composition. This program takes a ground-up approach to developing a highly versatile polymer platform that is driven by chemical innovation in order to incorporate the design features and flexibility needed for interfacing with biology. This is achieved by starting with the robust chemistry of ruthenium- based olefin metathesis and merging it with the power of substrate-directed chemical reactions. With this general strategy, incredibly robust ligation reactions have been designed to rapidly conjugate living polymers directly to other macromolecules, thereby removing the need to go through traditional click chemistry. This will lead to highly simplifying bioconjugation strategies, while also presenting opportunities for efficient ruthenium removal. This concept also enables the design of entirely new monomer families that give polymers with responsive chemistry in the backbone for programmable targeting, degradation, and cargo release. By changing the structure, fine tuning of degradation kinetics can be optimized and also redesigned to maintain biocompatibility. Lastly, this strategy will tackle a longstanding challenge in understanding the interaction of synthetic polymers with living system: architecture. A convergent strategy will be developed to give control of both the location and degree of branching in synthetic polymer systems. This will lead to the dissection of structure-property relationships in the polymer topology that is currently inaccessible with modern techniques. All of these methods combined will lead to a truly “medicinal chemistry” approach to polymer design where structures can be built, designed, and optimized with the specific end goals in mind.