Persistent　oxidative　stress　and　recurring　waves　of　inflammation　with　excessive　reactive　oxygen　species　(ROS)　and　free　radical　accumulation　could　be　generated　by　radiation.　Exposure　to　radiation　in　combina-tion　with　physical　injuries　such　as　wound　trauma　would　produce　a　more　harmful　set　of　medical　com-plications,　which　was　known　as　radiation　combined　with　skin　wounds　(RCSWs).　However,　little　atten-tion　has　been　given　to　RCSW　research　despite　the　unsatisfactory　therapeutic　outcomes.　In　this　study,　a　dual-nanoagent-loaded　multifunctional　hydrogel　was　fabricated　to　ameliorate　the　pathological　microen-vironment　associated　with　RCSWs.　The　injectable,　adhesive,　and　self-healing　hydrogel　was　prepared　by　crosslinking　carbohydrazide-modified　gelatin　(Gel-CDH)　and　oxidized　hyaluronic　acid　(OHA)　through　the　Schiff-base　reaction　under　mild　condition.　Polydopamine　nanoparticles　(PDA-NPs)　and　mesenchymal　stem　cell-secreted　small　extracellular　vesicles　(MSC-sEV)　were　loaded　to　relieve　radiation-produced　tissue　in-flammation　and　oxidation　impairment　and　enhance　cell　vitality　and　angiogenesis　individually　or　jointly.　The　proposed　PDA-NPs@MSC-sEV　hydrogel　enhanced　cell　vitality,　as　shown　by　cell　proliferation,　migra-tion,　colony　formation,　and　cell　cycle　and　apoptosis　assays　in　vitro　,　and　promoted　reepithelization　by　at-tenuating　microenvironment　pathology　in　vivo　.　Notably,　a　gene　set　enrichment　analysis　of　proteomic　data　revealed　significant　enrichment　with　adipogenic　and　hypoxic　pathways,　which　play　prominent　roles　in　wound　repair.　Specifically,　target　genes　were　predicted　based　on　differential　transcription　factor　expres-sion.　The　results　suggested　that　MSC-sEV-and　PDA-NP-loaded　multifunctional　hydrogels　may　be　promis-ing　nanotherapies　for　RCSWs.Statement　of　significanceThe　small　extracellular　vesicle　(sEV)　has　distinct　advantages　compared　with　MSCs,　and　polydopamine　nanoparticles　(PDA-NPs),　known　as　the　biological　materials　with　good　cell　affinity　and　histocompatibility　which　have　been　reported　to　scavenge　ROS　free　radicals.　In　this　study,　an　adhesive,　injectable,　self-healing,　antibacterial,　ROS　scavenging　and　amelioration　of　the　radiation　related　microenvironment　hydrogel　en-capsulating　nanoscale　particles　of　MSC-sEV　and　PDA-NPs　(PDA-NPs@MSC-sEV　hydrogel)　was　synthesized