Engineering HLA-G-targeted extracellular vesicles nanoplatform for enhanced cancer therapy through precise cancer drug delivery

Extracellular vesicles (EVs) hold great potential as a therapeutic delivery system for cancer treatment. Here, we develop an innovative targeted drug delivery platform, human leukocyte antigen-G-VHH antibody-modified EV (α-HLA-G-EV), to enhance therapeutic efficacy. A genetically engineered HEK293T stable clone is utilized to produce α-HLA-G-EV, which are subsequently loaded with chemotherapeutic agents to create HLA-G-targeting drug-loaded EVs (drug@α-HLA-G-EV). The cytotoxicity of drug@α-HLA-G-EV is assessed in various cancer cell lines, demonstrating superior tumor targeting and therapeutic efficacy compared to standard chemotherapies. In vivo experiments using xenograft NPG mouse models, established with MDA-MB-231 and U87 cell lines, further confirm the enhanced antitumor activity of Doxorubicin@α-HLA-G-EV and Temozolomide@α-HLA-G-EV. These findings are consistent with results observed in patient-derived breast cancer and GBM cell models. Additionally, drug@α-HLA-G-EV causes far less damage to normal organs than Lipo-Dox. These findings highlight the potential of α-HLA-G-EV as a versatile platform for precise and efficient cancer treatment. Extracellular vesicles (EVs) have shown potential as a therapeutic delivery system for cancer treatment. In here the authors have established HEK293T cells engineered with α-HLA-G VHH antibody-chimeric CD63 protein to promote the production of EVs that can augment the targeting of HLA-G-positive tumor cells