Specific drug delivery to metastatic tumors remains a great challenge for antimetastasis therapy. We herein report a bioengineered macrophage-based delivery system (LD-MDS) that can be preferentially delivered to lung metastases and intelligently transformed into nanovesicles and secondary nanovesicles for antimetastasis therapy. LD-MDS was prepared by anchoring a legumain-specific propeptide of melittin (legM) and cytotoxic soravtansine (DM4) prodrug onto the membrane of living macrophages. LD-MDS is responsively activated by legumain protease and converted into DM4-loaded exosome-like nanovesicles (DENs), facilitating efficient internalization by metastatic 4T1 cancer cells and considerable cell death. Afterward, the damaged 4T1 cells can release secondary nanovesicles and free drug molecules to destroy neighboring cancer cells. In vivo, LD-MDS displays superior targeting efficiency for lung metastatic lesions with diameters less than 100 μm and remarkably inhibits lung metastasis. This study provides a new opportunity to explore endogenous macrophages as living drug delivery vehicles with controlled drug release to target metastatic lung tumors.

中文翻译：

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生物工程巨噬细胞可以响应性地转变为纳米囊泡，以靶向肺转移

向转移性肿瘤的特异性药物递送仍然是抗转移疗法的巨大挑战。我们在此报告了一种基于生物工程的基于巨噬细胞的递送系统（LD-MDS），该系统可优先递送至肺转移瘤并智能转化为纳米囊泡和次级纳米囊泡以进行抗转移治疗。LD-MDS通过将蜂毒蛋白的豆蔻因特异性前肽（legM）和细胞毒性索拉丹汀（DM4）前药锚定在活的巨噬细胞膜上来制备。LD-MDS被豆科动物蛋白酶响应性激活，并转化为DM4负载的囊泡状纳米囊泡（DENs），从而促进了转移性4T1癌细胞的有效内在化和相当大的细胞死亡。之后，受损的4T1细胞可以释放出次级纳米囊泡并释放药物分子，从而破坏邻近的癌细胞。体内，LD-MDS对直径小于100μm的肺转移病变显示出优异的靶向效率，并显着抑制了肺转移。这项研究提供了一个新的机会来探索内源性巨噬细胞，将其作为活体药物输送工具，并控制药物的释放以靶向转移性肺肿瘤。