肿瘤细胞治疗研究
英文原题：Engineered extracellular vesicles with DR5 agonistic scFvs simultaneously target tumor and immunosuppressive stromal cells.
小细胞外囊泡（sEVs）是纳米级囊泡。
小细胞外囊泡（sEVs）是纳米级囊泡。死亡受体5（DR5）介导外源性凋亡。我们在来源于NK 细胞的sEVs表面工程化表达DR5激动性单链可变片段（scFv）。PDGFR跨膜结构域将DR5-scFv递送至sEVs表面。DR5-scFv sEVs迅速诱导不同类型的DR5+癌细胞、髓源性抑制细胞（MDSCs）和癌相关成纤维细胞（CAFs）凋亡。DR5-scFv sEVs在体外和体内特异性迁移至DR5+肿瘤。全身递送DR5-scFv sEVs显著抑制DR5+黑色素瘤、肝癌和乳腺癌的生长，并延长小鼠寿命且无明显毒性。DR5-scFv sEVs在体内显著比DR5抗体更有效。在器官型患者来源的黑色素瘤切片培养中，DR5-scFv sEVs有效抑制黑色素瘤细胞和MDSCs并激活CD8+ T细胞。我们的研究表明，DR5-scFv sEVs可通过靶向TME中的肿瘤细胞和免疫抑制性基质细胞来抑制肿瘤生长。
Small extracellular vesicles (sEVs) are nanosized vesicles. Death receptor 5 (DR5) mediates extrinsic apoptosis. We engineer DR5 agonistic single-chain variable fragment (scFv) expression on the surface of sEVs derived from natural killer cells. PDGFR transmembrane domain delivers DR5-scFvs to the surface of sEVs. DR5-scFv sEVs rapidly induce apoptosis of different types of DR5 + cancer cells, myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs). DR5-scFv sEVs migrate specifically to DR5 + tumors in vitro and in vivo. Systemic delivery of DR5-scFv sEVs significantly inhibits the growth of DR5 + melanoma, liver cancer, and breast cancer and prolongs mouse life span without significant toxicity. DR5-scFv sEVs are significantly more efficacious than DR5 antibodies in vivo. In organotypic patient-derived melanoma slice cultures, DR5-scFv sEVs effectively inhibit melanoma cells and MDSCs and activate CD8 + T cells. Our studies demonstrate that DR5-scFv sEVs can inhibit tumor growth by targeting tumor cells and immunosuppressive stromal cells in the TME.
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