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Bacterial outer membrane vesicles (OMVs) represent powerful immunoadjuvant nanocarriers with the capacity to reprogram the tumor microenvironment (TME) and activate immune responses. Here, we investigate a nanotherapeutic platform integrating immunostimulatory cytosine-phosphate-guanine oligodeoxynucleotides (CpG-ODNs, hereafter termed CpG) into mesoporous silica nanoparticles cloaked with OMVs (CpG@MSN-PEG/PEI@OMVs) for cancer immunotherapy. Systemic administration of these nanohybrids facilitates precise tumor targeting, induces antitumor cytokines such as IFNγ, and suppresses immunosuppressive cytokine TGF-β, reshaping the TME. Additionally, CpG@MSN-PEG/PEI@OMVs promote M1 macrophage polarization, dendritic cell maturation, and the generation of durable tumor-specific immune memory, resulting in pronounced tumor regression with minimal systemic toxicity. The platform demonstrates efficacy against metastatic and solid tumor models including 4T1 breast and MC38 colorectal cancers. Transcriptomic analyses reveal that CpG@MSN-PEG/PEI@OMVs enhance mitochondrial oxidative phosphorylation in T cells within tumor-draining lymph nodes, mitigating T cell exhaustion and restoring metabolic fitness. These results support the potential of CpG@MSN-PEG/PEI@OMVs as a modular nanoplatform to modulate innate and adaptive immunity in cancer immunotherapy.

Keywords: T cell exhaustion phenotypes; bacterial outer membrane vesicles; mesoporous silica nanoparticles; mitochondrial activity; tumor microenvironment.

Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica Doctoral Dissertation