In this work, a tumour targeted and multi-stimuli responsive drug delivery system has been developed for combining photoacoustic tomography imaging with chemo-phototherapy.We utilized a novel near infrared (NIR) resonant material-hollow mesoporous copper sulfide nanopaticles (HMCuS NPs) to encapsulate doxorubicin (DOX), after that, hyaluronie acid (HA) capped on the outer surface as a gatekeeper.Herein, HMCuS-HA could serve as a powerful contrast agent for photoacoustic tomography (PAT) to guide phototherapy by providing the identification of cancerous lesions.In vitro and in vivo studies, The nanoplatform (DOX/HMCuS-HA) pinpoint MCF-7 cells via CD44 receptor-mediated endocytosis pathway.Subsequently, iintracellular enzyme-responsive controlled release would happen in lysosome after the HA degradation by hyaluronidase.With near infrared (NIR) light irradiation, HMCuS NPs could not only effectively convert NIR light into heat for photothermal therapy, but also generate high levels of reactive oxygen species (ROS) for photodynamic therapy.In addition, NIR light and low pH environment could facilitate intracellular tunable drug release with remarkable spatial/temporal resolution, and thus synergistic combination of chemo-phototherapy can be simultaneously driven by a 808 nm laser irradiation, which brought out an outstanding therapeutic efficacy.In vivo optical imaging demonstrated that HMCuS-HA significantly enhanced targeting and accumulation capacity in tumour site.Furthermore, tumour-bearing mice treated with DOX/HMCuS-HA under NIR irradiation in vivo displayed the highest inhibition ratio of 88.87% and possessed an excellent therapeutic effect.Taken together, our present study of the turnour targeted and multi-stimuli responsive drug delivery system provides new insights into theranostic biomedical applications.