Nanotheranostics　with　integrated　imaging　functions　can　help　monitor　nanoparticle　accumulation　in　tumors,　thus　achieving　synergism　and　higher　therapeutic　accuracy　in　cancer　therapy.　However,　it　remains　challenging　to　monitor　the　release　of　therapeutic　drugs　in　real　time　from　a　nanoparticulate　drug　delivery　system　(nano-DDS)　in　the　body.　Herein,　we　developed　a　nano-DDS　for　fluorescence　imaging　in　the　second　near-infrared　window　(NIR-II)　region,　which　can　be　used　for　monitoring　the　responsive　release　of　drugs　and　cancer-targeted　combined　photodynamic　and　chemotherapy.　There　is　a　linear　correlation　between　the　cumulative　release　of　the　drug　and　the　NIR-II　fluorescence　intensity.　Moreover,　hyaluronidase/glutathione　dual-response　RGD-SS-DOX/Ce6@HA-IR-1061　(RSSDCHI)　exhibited　a　higher　tumor-to-normal-tissue　ratio　in　NIR-II　fluorescence　imaging　and　enhanced　antitumor　efficacy　in　vivo.　This　makes　it　possible　to　visualize　drug　release　at　the　cellular　level　by　the　nanocomposites　and　to　predict　the　treatment　effect　according　to　the　NIR-II　fluorescence　intensity　in　the　tumor　site,　serving　as　a　promising　nanoplatform　for　precision　nanomedicine.　©　2022　American　Chemical　Society