The　human　epidermal　growth　factor　receptor-2-positive　(HER2+)　type　is　aggressive　and　has　poor　prognosis.　Although　anti-HER2　therapy　alone　or　in　combination　with　other　treatment　regimens　showed　significant　improvement　in　survival　outcomes,　breast　cancer　patients　are　still　suffering　from　tumor　relapse　and　severe　dose-limiting　side　effects.　Thus,　there　is　still　an　unmet　challenge　to　develop　effective　therapeutic　agents　for　HER2+　breast　cancer　treatment　with　minimized　side　effects.　Herein,　we　produced　a　stimuli-responsive　and　tumor-targeted　hyaluronic　acid　(HA)　nanocomplex　that　combined　HER2　blockade　and　chemotherapy　for　effective　HER2+　breast　cancer　therapy.　A　hydrophobic　NIR-II　dye,　IR1048,　was　covalently　linked　with　HA　to　form　a　spherical　HA-IR1048　nanoparticle　(HINP),　with　Herceptin　conjugated　on　the　surface　and　paclitaxel　(PTX)　encapsulated　inside.　The　fluorescent　signals　from　the　yielding　Her-HINP/PTX　are　quenched　originally,　but　a　strong　NIR-II　signal　is　generated　when　HINP　is　degraded　by　the　hyaluronidase　that　is　overexpressed　in　breast　tumors,　thus　allowing　the　tracking　and　visualization　of　Herceptin　and　PTX　accumulation.　Her-HINP/PTX　peaked　in　HER2+　tumors　at　24　h　post　injection　as　imaged　by　NIR-II　fluorescent　imaging.　A　significantly　improved　tumor　growth　inhibition　effect　was　observed　after　five　systemic　treatments　compared　to　single　PTX　(3.71　±　0.41　times)　or　Herceptin　(5.98　±　0.51　times)　treatment　in　a　HER2-overexpressed　breast　cancer　mouse　model　with　prolonged　survival.　Collectively,　the　designed　Her-HINP/PTX　presents　a　new　hyaluronidase-responsive　and　HER2　blockade　nanoformulation　that　can　visualize　the　accumulation　of　nanocomplexes　and　release　drugs　inside　tumors　for　combined　HER2+　breast　cancer　therapy　with　a　great　promise　for　translational　study.　Statement　of　significance:　The　high　expressions　of　a　protein　called　human　epidermal　growth　factor　receptor　2　(HER2)　in　breast　tumors　make　this　subtype　of　cancer　aggressive.　Currently,　chemotherapy　combined　with　a　HER2　antibody,　Herceptin,　is　a　preferred　approach　for　HER2-positive　breast　cancer　therapy.　However,　these　breast　cancer　patients　still　suffer　from　tumor　relapse　and　severe　side　effects　because　various　therapeutic　agents　have　inherent　different　biodistributions,　resulting　in　insufficient　treatment　effects　and　unfavorable　normal　organ　uptake　of　these　therapeutic　agents.　Herein,　we　produced　a　nanocomplex　carrying　both　Herceptin　and　chemotherapy　drug　to　simultaneously　deliver　two　drugs　into　tumors　for　efficient　HER2+　tumor　treatment　with　minimized　side　effects,　providing　new　insights　for　designing　a　combined　therapy　strategy.　©　2022