The chemotherapy combined with photothermal therapy has been a favorable approach for the treatment of breast cancer.In present study,nanoparticles with the characteristics of photothermal/matrix metalloproteinase-2(MMP-2)dual-responsive,tumor targeting,and size-variability were designed for enhancing the antitumor efficacy and achieving“on-demand”drug release markedly.Based on the thermal sensitivity of gelatin,we designed a size-variable gelatin nanoparticle(GNP)to encapsulate in-docyanine green(ICG)and doxorubicin(DOX).Under an 808 nm laser irradiation,GNP-DOX/ICG re-sponded photothermally and swelled in size from 71.58 士 4.28 to 160.80 ± 9.51 nm,which was beneficial for particle retention in the tumor sites and release of the loaded therapeutics.Additionally,GNP-DOX/ICG showed a size reduction of the particles to 33.24 士 4.11 nm and further improved drug release with the degradation of overexpressed MMP-2 in tumor.In the subsequently performed in vitro experiments,it was confirmed that GNP-DOX/ICG could provide a therapeutic effect that was enhanced and synergistic.Consequently,GNP-DOX/ICG could efficiently suppress the growth of 4T1 tumor in vivo.In conclusion,this study may provide a promising strategy in the rational design of drug delivery nanosystems based on gelatin for chemo-photothermal therapy to achieve synergistically enhanced ther-apeutic efficacy against breast cancer.