The treatment of chronic wounds is still a challenge worldwide. Here, inspired by mechanically induced embryonic wound healing, we design a mechanically active small intestinal submucosa based hydrogel (SIS-PNIPAm). The mechanical activity, biocompatibility, and bioactivity (angiogenesis and immunoregulation) of the SIS-PNIPAm hydrogel enable the fast healing of diabetic rat full-thickness wounds.