Multi-functional nanoparticles with targeting and chemo-photothermal features are attractive materials for the development of therapeutics. In this study, thermaland pH-sensitive nanoparticles loaded with two drugs were fabricated for controlled drug release. For synthesis of nanoparticles, we first prepared a PAMAM dendrimer cluster, which could provide large core space, and then sequentially loaded indocyanine green (ICG, a photothermal agent) and doxorubicin (DOX, a chemotherapeutic agent) premixed with polyacrylic acid (PAA) to the dendrimer cluster through ionic interactions. This self-assembling strategy yielded a high drug-loading content for both DOX (19.1 +/- 0.4%) and ICG (54 +/- 1%). Subsequently, PEG and Herceptin were covalently attached to nano particles to promote their bio-recognition by HER2-overexpressing cancer cells. DOX was released by changing pH from 7.4 to 5; DOX release was markedly enhanced by NIR (808 nm) laser irradiation. Conjugation with Herceptin could enhance specific attachment and accumulation of nanoparticles in tumor cells. Under NIR laser irradiation, ICG served as a remote-controlled trigger to generate considerable heat that caused severe physical damage and extensive cell apoptosis. Furthermore, after NIR laser irradiation, drug delivery and penetration of the nanoparticles into tumor spheroids were enhanced, indicating the potential therapeutic application of the newly developed nanoparticles. (c) 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).