Upon near-infrared (NIR) light irradiation, the Nd doping derived down-conversion luminescence (DCL) in NIR region and thermal effect are extremely fascinating in bio-imaging and photothermal therapy (PTT) fields. However, the concentration quenching induced opposite changing trend of the two properties makes it difficult to get desired DCL and thermal effect together in one single particle. In this study, we firstly designed a unique NaGdF:0.3%Nd@NaGdF@NaGdF:10%Yb/1%Er@NaGdF:10%Yb @NaNdF:10%Yb multiple core-shell structure. Here the inert two layers (NaGdF and NaGdF:10%Yb) can substantially eliminate the quenching effects, thus achieving markedly enhanced NIR-to-NIR DCL, NIR-to-Vis up-conversion luminescence (UCL), and thermal effect under a single 808 nm light excitation simultaneously. The UCL excites the attached photosensitive drug (Au nanoclusters) to generate singlet oxygen (O) for photodynamic therapy (PDT), while DCL with strong NIR emission serves as probe for sensitive deep-tissue imaging. The in vitro and in vivo experimental results demonstrate the excellent cancer inhibition efficacy of this platform due to a synergistic effect arising from the combined PTT and PDT. Furthermore, multimodal imaging including fluorescence imaging (FI), photothermal imaging (PTI), and photoacoustic imaging (PAI) has been obtained, which is used to monitor the drug delivery process, internal structure of tumor and photo-therapeutic process, thus achieving the target of imaging-guided cancer therapy.