Stem cells are attractive cell sources for tissue regeneration due to their unique capacity of differentiation, as well as their ability to contribute to tissue repair via paracrine signaling. However, the efficacy of applying stem cells alone to achieve robust tissue regeneration in situ remains limited, often due to lack of appropriate microenvironmental cues to guide desirable cellular fates. In this talk, Yang will discuss examples of her research on how to employ biomaterials to address these challenges using two strategies. In the first strategy, she engineers stem cell microenvironments from Ðoutside-inÓ by developing novel biomaterials as artificial extracellular matrix. Using a Ðlego-buildingÓ approach, her platforms allow fabrication of biomaterials modules with independently tunable cell niche properties including biochemical, mechanical and topographical cues. Such biomaterials can provide useful tools to enhance cell engraftment, guide desirable cell fates and provide tissue-mimicking mechanical properties. In the second strategy, she harnesses stem cells as drug delivery vehicles and its ability to catalyze tissue regeneration via paracrine signaling. Yang can further engineer the paracrine signaling of stem cells from “inside-out” using biodegradable polymeric nanoparticle-mediated non-viral gene delivery. Potential applications of such stem cell and biomaterials-based strategies for treating musculoskeletal diseases, cardiovascular diseases, and cancer will be demonstrated using relevant animal models.