Nanoscale　metal-organic　frameworks　(nano　MOFs)　have　emerged　as　a　promising　biomedical　nanoplatform　because　of　their　unique　properties.　However,　the　exploration　of　nano　MOFs　in　photoacoustic　(PA)　imaging　is　still　limited.　Here,　a　novel　hydrogen　sulfide　(H2S)-activated　nano　copper-based　MOF　(Cu-MOF)　was　developed　as　a　near-infrared　(NIR)　ratiometric　PA　probe　forin　vivomonitoring　of　endogenous　H2S　level　and　orthotopic　colorectal　cancer　imagingvia　in　situreaction　of　nano　Cu-MOFs　with　endogenous　H2S　that　is　closely　associated　with　tumor　growth　and　proliferation　in　colon　cancer.　The　synthesized　nano　Cu-MOFs　displayed　excellent　PA　responsiveness　towards　tumor　H2S　level　with　high　selectivity　and　rapid　kinetics.　The　result　suggests　the　developed　probe　may　provide　a　unique　opportunity　to　investigate　the　malignant　behaviors　of　H2S-associated　eventsin　vivo.