Mitochondria-targeting　nanoparticles　have　proven　to　be　promising　platforms　for　cancer　therapy.　However,　precise　mitochondria　targeting　in　the　complex　tumor　environment　is　still　challenging　and　requires　more　ingenious　design.　Herein,　we　developed　the　glutathione　(GSH)-responsive　nanoagents　to　target　mitochondria　in　tumor　cells　precisely　for　photothermal-enhanced　chemodynamic　therapy　(CDT).　The　nanoagents　were　designed　by　preparing　the　cubic　shape　of　CuFeS2　nanoparticles　that　sequentially　modified　with　mitochondrial-targeting　peptide　(KLAK)　and　integrin-targeting　peptide　(RGD),　which　KLAK　and　RGD　were　covalently　conjugated　via　a　disulfide　bond.　After　being　endocytosed　into　integrin-overexpressed　tumor　cells,　disulfide　bond　was　broken　and　RGD　was　separated　from　the　nanoagents　in　the　presence　of　overexpressed　GSH.　Then,　the　exposure　of　KLAK　on　the　surface　further　aid　the　rustling　nanoagents　to　target　mitochondria.　Under　NIR　laser　irradiation,　the　surrounding　temperature　of　the　nanoagents　would　rise　due　to　their　excellent　photothermal　effect,　resulting　in　the　improvement　of　the　Fenton　reaction　from　the　CuFeS2.　It　was　well　demonstrated　that　this　photothermal-enhanced　chemodynamic　therapy　nanoplatform　could　effectively　damage　the　mitochondrial　function　and　further　induce　the　apoptosis　of　tumor　cells.　As　a　therapeutic　platform　with　both　tumor/mitochondria-targeting　and　PTT-enhanced　CDT,　our　study　has　provided　a　new　path　in　the　field　of　cancer　therapy.　©　2022　The　Author(s)