Shape amphiphiles refer to a class of molecular conjugates composed by distinct building blocks with incommensurate shapes and chemical interactions. Whilst extensive efforts have been devoted to the solid state self-assembly and nanolithography applications of shape amphiphiles, only very limited examples of their usage in the biomedical field have been explored. In this work, we reported a series of gallic acid functionalized polyhedral oligomeric silsesquioxane (POSS)-based shape amphiphiles with various macromolecular architectures for efficient and accelerated wound healing. These antioxidant giant amphiphiles demonstrated good biocompatibility and strong free radical scavenging activity to prevent cell oxidative damage and then promote wound recovery. We describe these POSS-based antioxidant shape amphiphiles in an initial proof-of-concept study and propose that this family of functional giant amphiphiles will be useful in regenerative biomedicine.