Villar-Álvarez, EvaGolán‐Cancela, IrenePardo Montero, AlbertoVelasco Rodríguez, BrendaFernández‐Vega, JavierCambón Freire, AdrianaAl‐Modlej, AbeerTopete Camacho, AntonioBarbosa Fernández, SilviaCostoya Puente, José AntonioTaboada Antelo, Pablo2023-11-142023-11-142023-08-26Small 2023, 23039341613-6810http://hdl.handle.net/10347/31270Treatment failure in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2) is associated mainly to the upregulation of human epidermal growth factor receptor 3 (HER3) oncoprotein linked to chemoresitence. Therefore, to increase patient survival, here a multimodal theranostic nanoplatform targeting both HER2 and HER3 is developed. This consists of doxorubicin-loaded branched gold nanoshells functionalized with the near-infrared (NIR) fluorescent dye indocyanine green, a small interfering RNA (siRNA) against HER3, and the HER2-specific antibody Transtuzumab, able to provide a combined therapeutic outcome (chemo- and photothermal activities, RNA silencing, and immune response). In vitro assays in HER2+/HER3+ SKBR-3 breast cancer cells have shown an effective silencing of HER3 by the released siRNA and an inhibition of HER2 oncoproteins provided by Trastuzumab, along with a decrease of the serine/threonine protein kinase Akt (p-AKT) typically associated with cell survival and proliferation, which helps to overcome doxorubicin chemoresistance. Conversely, adding the NIR light therapy, an increment in p-AKT concentration is observed, although HER2/HER3 inhibitions are maintained for 72 h. Finally, in vivo studies in a tumor-bearing mice model display a significant progressively decrease of the tumor volume after nanoparticle administration and subsequent NIR light irradiation, confirming the potential efficacy of the hybrid nanocarriereng© 2023 The Authors. Small published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposesAtribución-NoComercial 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc/4.0/HER3 HyperphosphorylationBreast cancerReceptor 3OncoproteinsTherapyjournal article10.1002/smll.2023039341613-6829open access