As　a　clinical　anti-glioma　agent,　the　therapeutic　effect　of　carmustine　(BCNU)　was　largely　decreased　because　of　the　drug　resistance　mediated　by　O6-alkylguanine-DNA　alkyltransferase　(AGT)　and　the　blood-brain　barrier　(BBB).　To　overcome　these　obstacles,　we　synthesized　a　BCNU-loaded　hypoxia/esterase　dual　stimulus-activated　nanomicelle,　abbreviated　as　T80-HACB/BCNU　NPs.　In　this　nano-system,　Tween　80　acts　as　the　functional　coating　on　the　surface　of　the　micelle　to　facilitate　transport　across　the　BBB.　Hyaluronic　acid　(HA)　with　active　tumor-targeting　capability　was　linked　with　the　hypoxia-sensitive　AGT　inhibitors　(O6-azobenzyloxycarbonyl　group)　via　an　esterase-activated　ester　bond.　The　obtained　T80-HACB/BCNU　NPs　had　an　average　particle　size　of　232.10　±　10.66　nm,　the　zeta　potential　of　−18.13　±　0.91　mV,　and　it　showed　high　drug　loading　capacity,　eximious　biocompatibility　and　dual　activation　of　hypoxia/esterase　drug　release　behavior.　The　obtained　T80-HACB/BCNU　NPs　showed　enhanced　cytotoxicity　against　hypoxic　T98G　and　SF763　cells　with　IC50　at　132.2　μM　and　133.1　μM,　respectively.　T80　modification　improved　the　transportation　of　the　micelle　across　an　in　vitro　BBB　model.　The　transport　rate　of　the　T80-HACB/Cou6　NPs　group　was　12.37　%,　which　was　7.6-fold　(p＜0.001)　higher　than　the　micelle　without　T80　modification.　T80-HACB/BCNU　NPs　will　contribute　to　the　development　of　novel　CENUs　chemotherapies　with　high　efficacy.　©　2024　Elsevier　B.V.