Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has no therapeutic targets, relies on chemotherapeutics for treatment, and is in dire need of novel therapeutic approaches for improved patient outcomes. Extracellular vesicles (EVs) serve as intercellular communicators and have been proposed as ideal drug delivery vehicles. Here, EVs were engineered with RNA nanotechnology to develop TNBC tumor inhibitors. Using super resolved-structured illumination microscopy, EVs were optimized for precise Survivin small interfering RNA (siRNA) conjugated to chemotherapeutics loading and CD44 aptamer ligand decoration, thereby enhancing specificity toward TNBC cells. Conventional treatments typically employ chemotherapy drugs gemcitabine (GEM) and paclitaxel (PTX) at dosages on the order of mg/kg respectively, per injection (intravenous) in mice. In contrast, engineered EVs encapsulating these drugs saw functional tumor growth inhibition at significantly reduced concentrations: 2.2 μg/kg for GEM or 5.6 μg/kg for PTX, in combination with 21.5 μg/kg survivin-siRNA in mice. The result is a substantial decrease in the chemotherapeutic dose required, by orders of magnitude, compared with standard regimens. In vivo and in vitro evaluations in a TNBC orthotopic xenograft mouse model demonstrated the efficacy of this decreased dosage strategy, indicating the potential for decreased chemotherapy-associated toxicity.

中文翻译：

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用于组合 TNBC 治疗的工程化细胞外囊泡：SR-SIM 指导设计可大幅减少药物剂量


三阴性乳腺癌 （TNBC） 是乳腺癌的一种侵袭性亚型，没有治疗靶点，依赖化疗药物治疗，迫切需要新的治疗方法来改善患者的预后。细胞外囊泡 （EV） 作为细胞间通讯器，已被提议作为理想的药物递送载体。在这里，使用 RNA 纳米技术对 EV 进行工程改造以开发 TNBC 肿瘤抑制剂。使用超分辨结构照明显微镜，对 EV 进行了优化，以用于与化疗药物负载和 CD44 适配体配体修饰偶联的精确存活素小干扰 RNA （siRNA），从而增强对 TNBC 细胞的特异性。常规治疗通常采用化疗药物吉西他滨 （GEM） 和紫杉醇 （PTX），剂量分别为 mg/kg，小鼠每次注射（静脉内）。相比之下，封装这些药物的工程化 EV 在显著降低的浓度下显示出功能性肿瘤生长抑制：GEM 为 2.2 μg/kg 或 PTX 为 5.6 μg/kg，小鼠中为 21.5 μg/kg 存活素-siRNA。结果是与标准方案相比，所需的化疗剂量大幅减少几个数量级。 TNBC 原位异种移植小鼠模型的体内和 体外评估证明了这种减少剂量策略的有效性，表明有可能降低化疗相关毒性。