HER family members are interdependent and functionally compensatory. Simultaneously targeting EGFR/HER2/HER3 by antibody combinations has demonstrated superior treatment efficacy over targeting one HER receptor. However, antibody combinations have their limitations, with high immunogenicity and high cost. In this study, we have developed a three-in-one nucleic acid aptamer-small interfering RNA (siRNA) chimera, which targets EGFR/HER2/HER3 in one molecule. This inhibitory molecule was constructed such that a single EGFR siRNA is positioned between the HER2 and HER3 aptamers to create a HER2 aptamer-EGFR siRNA-HER3 aptamer chimera (H2EH3). EGFR siRNA was delivered into HER2-expressing cells by HER2/HER3 aptamer-induced internalization. HER2/HER3 aptamers act as antagonist molecules for blocking HER2 and HER3 signaling pathways and also as tumor-targeting agents for siRNA delivery. H2EH3 enables down-modulation of the expression of all three receptors, thereby triggering cell apoptosis. In breast cancer xenograft models, H2EH3 is able to bind to breast tumors with high specificity and significantly inhibits tumor growth via either systemic or intratumoral administration. Owing to low immunogenicity, ease of production, and high thermostability, H2EH3 is a promising therapeutic to supplement current single HER inhibitors and may act as a treatment for HER2⁺ breast cancer with intrinsic or acquired resistance to current drugs.

她的家庭成员是相互依存和功能补偿的。通过抗体组合同时靶向 EGFR/HER2/HER3 已证明比靶向一种 HER 受体具有更好的治疗效果。然而，抗体组合有其局限性，免疫原性高且成本高。在这项研究中，我们开发了一种三合一核酸适体-小干扰RNA（siRNA）嵌合体，该嵌合体在一个分子中靶向EGFR/HER2/HER3。构建该抑制分子，使得单个EGFR siRNA位于HER2和HER3适体之间，以产生HER2适体-EGFR siRNA-HER3适体嵌合体(H2EH3)。通过 HER2/HER3 适体诱导的内化，将 EGFR siRNA 递送至表达 HER2 的细胞中。HER2/HER3 适配体可作为阻断 HER2 和 HER3 信号通路的拮抗剂分子，也可作为 siRNA 递送的肿瘤靶向剂。H2EH3 能够下调所有三种受体的表达，从而引发细胞凋亡。在乳腺癌异种移植模型中，H2EH3 能够以高特异性结合乳腺肿瘤，并通过全身或瘤内给药显着抑制肿瘤生长。由于免疫原性低、易于生产和高热稳定性，H2EH3 是一种很有前景的治疗药物，可以补充现有的单一 HER 抑制剂，并可以作为对现有药物具有内在或获得性耐药性的 HER2 + 乳腺癌的治疗^方法。