Interruption of any part of the complex and highly orchestrated stages of tissue repair leads to increased morbidity and mortality, such as in chronic diabetic wounds and traumatic spinal cord injuries. My research focuses on biomaterial scaffold and recombinant protein engineering to harness mechanisms of repair in skin and spinal cord injuries to accelerate healing kinetics, enhance functional outcomes, and preserve tissue integrity. The first vignette will focus on the combinatorial treatment of acute and diabetic wounds with silk fibroin nanocomposites and small molecule bioactives, the identification of novel, emergent reparative biomaterial-tissue responses, and the concurrent discovery of a wound- and biomaterial-responsive epidermal serine protease inhibitor (serpin) with a novel role in tissue repair. The second vignette will discuss the development of a tunable, drug-loaded silk fibroin biomaterial wound dressing to augment extracellular ATP-evoked inflammasome activity for diabetic wound repair. In the last vignette, I will describe the development of immunomodulating biologics of viral origin, including biomaterial formulations for sustained delivery and protein engineering strategies to enhance therapeutic properties, highlighting their efficacy in accelerating and improving dermal wound healing and in promoting functional recovery with reduced tissue loss in spinal cord injury. This talk will emphasize the advantages of synergizing fundamental and applied studies to engineer bio-inspired solutions to widespread human health problems.