乳腺癌治疗失败主要与高表达人表皮生长因子受体2（HER2）相关，此与与化疗耐药性有关的人表皮生长因子受体3（HER3）致癌蛋白的上调有关。因此，为了提高患者的存活率，开发了一种同时靶向HER2和HER3的多模态治疗纳米平台。该平台由负载阿霉素的分枝状金纳米壳组成，其功能化了近红外（NIR）荧光染料吲哚菁绿（indocyanine green），还含有针对HER3的小干扰RNA（siRNA）和针对HER2的特异性抗体Transtuzumab，能够提供联合治疗效果（化疗和光热活性、RNA沉默和免疫反应）。体外实验表明，在HER2+/HER3+ SKBR-3乳腺癌细胞中，释放的siRNA有效沉默了HER3，并由Trastuzumab抑制了HER2致癌蛋白，同时还观察到蛋白激酶Akt的苏氨酸/苏氨酸蛋白激酶（p-AKT）的降低，该蛋白通常与细胞存活和增殖有关，有助于克服阿霉素的化疗耐药性。相反地，在加入近红外光疗法时，观察到p-AKT浓度的增加，尽管HER2/HER3的抑制作用在72小时内得以保持。最后，在肿瘤携带的小鼠模型中进行的体内研究显示，在纳米颗粒给药和随后的近红外光照射后，肿瘤体积显著减小，证实了这种混合纳米载体的潜在疗效。© 2023 The Authors. Small published by Wiley-VCH GmbH.

Treatment 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 nanocarrier.© 2023 The Authors. Small published by Wiley-VCH GmbH.