Exosomes (Exo) hold great promise as endogenous nanocarriers that can deliver biological information between cells. However, Exo are limited in terms of their abilities to target specific recipient cell types. We developed a strategy to isolate Exo exhibiting increased binding to integrin αvβ3. Binding occurred through a modified version of a disintegrin and metalloproteinase 15 (A15) expressed on exosomal membranes (A15-Exo), which facilitated co-delivery of therapeutic quantities of doxorubicin (Dox) and cholesterol-modified miRNA 159 (Cho-miR159) to triple-negative breast cancer (TNBC) cells, both in vitro and in vivo. The targeted A15-Exo were derived from continuous protein kinase C activation in monocyte-derived macrophages. These cell-derived Exo displayed targeting properties and had a 2.97-fold higher production yield. In vitro, A15-Exo co-loaded with Dox and Cho-miR159 induced synergistic therapeutic effects in MDA-MB-231 cells. In vivo, miR159 and Dox delivery in a vesicular system effectively silenced the TCF-7 gene and exhibited improved anticancer effects, without adverse effects. Therefore, our data demonstrate the synergistic efficacy of co-delivering miR159 and Dox by targeted Exo for TNBC therapy.

中文翻译：

---

功能性外泌体介导的阿霉素和疏水修饰的microRNA 159的共同递送，可用于三阴性乳腺癌治疗。

外来体（Exo）作为可以在细胞之间传递生物学信息的内源性纳米载体具有广阔的前景。但是，Exo在针对特定受体细胞类型的能力方面受到限制。我们开发了一种策略来分离表现出与整联蛋白αvβ3结合增加的Exo。结合是通过外体膜（A15-Exo）上表达的整合素和金属蛋白酶15（A15）的修饰形式发生的，这有助于将治疗量的阿霉素（Dox）和胆固醇修饰的miRNA 159（Cho-miR159）共递送体外和体内三阴性乳腺癌（TNBC）细胞。靶向的A15-Exo衍生自单核细胞衍生巨噬细胞中的连续蛋白激酶C活化。这些细胞来源的Exo表现出靶向特性，并具有2.97倍的高产量。体外，与Dox和Cho-miR159共装载的A15-Exo在MDA-MB-231细胞中诱导协同治疗作用。在体内，miR159和Dox在水泡系统中的递送有效地使TCF-7基因沉默，并表现出改善的抗癌作用，而没有副作用。因此，我们的数据证明了靶向Exo对TNBC治疗共同递送miR159和Dox的协同功效。