Engineered biomimetic vesicles induce cuproptosis and disrupt efferocytosis for metastatic adenoid cystic carcinoma immunotherapy

Adenoid cystic carcinoma (ACC) is a lethal salivary gland malignant neoplasm. Lung metastasis is the primary cause of mortality in ACC patients while there is no effective treatment available at present. In this study, a precise and biomimetic nanoplatform, CG/MC/U-M, is designed to combine cuproptosis, gas therapy and immunotherapy against metastatic adenoid cystic carcinoma. CG/MC/U-M was derived from ACC cell membranes, encapsulating carbonyl manganese (Mn(2)(CO)(10)), efferocytosis inhibitor (UNC2025) and metal-phenolic network (CuGA). After targeted accumulation in pulmonary metastases and cellular internalization by ACC cells, CG/MC/U-M was degraded and released the contents. The released CuGA depleted cellular GSH and triggered cuproptosis, inducing mitochondrial damage which was further exacerbated by the release of carbon monoxide (CO) from Mn(2)(CO)(10). Meanwhile, UNC2025-mediated efferocytosis blockade promoted immunogenic cell death (ICD) through damage associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs) release, while Mn(2+) from Mn(2)(CO)(10) activated the STING pathway and stimulated antitumor immunity. This dual-action mechanism synergistically reprogramed the immunosuppressive microenvironment, promoting the maturation of dendritic cells (DCs), repolarizing macrophages to the M1 phenotype, and resulting in a significant increase in the infiltration of CD8(+) T cells. Both in vitro and in vivo studies indicated that the CG/MC/U-M system effectively targeted ACC pulmonary metastases and inhibited ACC progression within lung tissues, underscoring its potential for personalized adenoid cystic carcinoma (ACC) therapy.