The　ascendant　danger　of　bacterial　infections　has　resulted　in　an　urgent　requirement　for　developing　new　antibacterial　approaches.　Recently,　nitric　oxide　(NO)　has　shown　a　broad-spectrum　antimicrobial　activity　while　avoiding　resistance.　However,　achieving　effective　NO-based　antibacterial　therapies　remains　challenging,　mired　by　the　safety　concerns　of　NO　donor,　residual　toxicity　by　the　ingredients,　or　complicated　procedures.　Herein,　a　self-activated　NO-releasing　hydrogel　depot　is　fabricated　by　Ca2+-crosslinked　sodium　alginate　doped　with　CaO2　nanoparticles,　L-arginine,　and　oxidized　mesoporous　carbon　nanoparticles　(OMCN)　for　photothermal　enhanced　bacteria　killing.　The　locally　concentrated　H2O2,　generated　from　the　reaction　of　CaO2　nanoparticles　and　water,　could　oxidize　L-arginine　to　release　NO.　Meanwhile,　benefiting　from　the　remarkable　photothermal　effect　of　OMCN,　the　hybrid　hydrogel　possesses　a　synergistic　sterilization　behavior　in　combating　both　Gram-negative　Escherichia　coli　and　Gram-positive　Staphylococcus　aureus　bacteria　in　vitro.　Moreover,　the　dual　therapeutic　hydrogel　displays　high　efficiency　in　treatment　of　bacteria-infected　mice　with　back　wound　model　while　showing　no　distinct　toxicity.　In　addition,　the　restricted　environment　of　hydrogel　makes　it　easy　to　remove　all　the　components　from　the　infected　wound,　alleviating　possible　side　effects　from　exogenous　H2O2.　As　such,　the　designed　NO-synergistic　photothermal　hydrogel　provides　a　promising　strategy　for　treating　bacterial　infections.　[Figure　not　available:　see　fulltext.]　©　2022,　Tsinghua　University　Press.