Hybrid bioinspired nanovescicles target tumor endothelial cells and regulate immuno-microenvironment for triple-negative breast cancer therapy

BACKGROUND: The treatment of triple-negative breast cancer (TNBC) remains challenging. Conventional anti-angiogenic therapies, which aim to disrupt the tumor’s blood supply, are often hampered by limited efficacy and drug resistance. Innovative strategies that specifically target the unique phenotype of tumor vascular endothelial cells (TVECs) are urgently needed. METHODS: We developed peroxide-treated hybrid membrane bio-nanovesicles (ox-HyV) by fusing membranes from human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) and breast cancer cells. The vesicles were characterized for size, morphology, and protein composition. Their targeting efficiency to TVECs was validated both in vitro and in vivo using immunofluorescence and small animal imaging. The functional effects on TVEC secretion, cGAS-STING pathway activation, and immune cell recruitment were assessed via ELISA, western blot, flow cytometry, and immunofluorescence. The anti-tumor efficacy and survival benefit were evaluated in a murine TNBC model. RESULTS: ox-HyVs specifically targeted and were internalized by TVECs. They reprogrammed the secretory phenotype of TVECs by delivering key molecular cargoes, notably miR-429, which subsequently downregulated Bcl2 and activated the cGAS-STING pathway. This activation triggered a robust innate immune response and promoted the infiltration of cytotoxic T cells into tumors. In vivo, treatment with ox-HyVs significantly inhibited tumor growth and extended survival in a TNBC mouse model. CONCLUSION: We have developed a novel bio-nanovesicle, ox-HyV, that represents a significant advancement over previous hybrid membrane systems. Unlike conventional hybrid vesicles designed primarily for drug delivery, ox-HyV is engineered through peroxidation to be intrinsically immunogenic, enabling it to directly reprogram the tumor vasculature and activate the cGAS-STING pathway via its endogenous miRNA cargo. This self-adjuvating, multimodal mechanism effectively converts the immunosuppressive tumor microenvironment into an immunoreactive one. Our study not only presents a potent new therapeutic candidate but also establishes a broadly applicable platform technology for vascular-targeted immunotherapy, with strong promise for clinical translation in TNBC and other solid tumors.