Despite　advances　in　the　development　of　osteo-regenerative　biomaterials,　current　products　are　vulnerable　to　stress-induced　formation　of　cracks,　resulting　in　the　loss　of　functionality　and　a　limited　lifespan.　In　the　present　study,　a　strategy　based　on　host-guest　assembly　was　developed　to　fabricate　a　silk　fibroin-based　inorganic-organic　hybrid　hydrogel　(termed　SF@HG@HA)　in　which　silk　fibroin　was　used　as　a　polymer　template　to　tether　host　(β-cyclodextrin)　and　guest　(cholesterol)　monomers,　respectively.　Due　to　dynamic　host-guest　interactions,　the　prepared　hydrogel　could　repair　itself　spontaneously　when　damaged,　without　the　assistance　of　any　external　stimuli,　mimicking　the　self-healing　characteristics　of　native　bone　tissue.　Furthermore,　the　efficient　energy　dissipation　mechanism　provided　by　the　host-guest　crosslinking　strategy　endowed　the　hydrogel　with　robust　mechanical　properties　to　bear　substantial　mechanical　loading.　SF@HG@HA　was　shown　to　support　cell　proliferation　and　osteogenic　differentiation　in　vitro　and　accelerate　bone　regeneration　in　critical-size　rat　femoral　defects　in　vivo.　Together,　the　silk　fibroin-based　self-healing　hydrogel　with　robust　mechanical　properties　shows　potential　applications　in　the　reconstruction　of　bone　defects,　which　may　provide　new　directions　for　the　design　of　functional　biomaterials　for　tissue　regeneration.　©　2020