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Research Article: Modular engineered outer membrane vesicles for synergistic cancer immunotherapy via PD-L1 blockade and epigenetic reprogramming

Date Published: 2026-07-31

Abstract:
Immune checkpoint inhibitors have significantly improved therapeutic outcomes in advanced melanoma; however, their clinical efficacy is greatly limited by low overall response rates and the primary or acquired resistance. Here, we developed a SpyCatcher-engineered bacterial outer membrane vesicle (OMV) platform for the co-delivery of a PD-1/PD-L1 inhibitor, the D-PPA1 peptide, and the epigenetic regulator zebularine (Zeb). The resulting co-delivery system, OMV@PPA/Zeb, effectively blocked PD-1/PD-L1 interactions and markedly upregulated melanoma-associated antigens, including CD146 and TRP1, in melanoma cells. In a subcutaneous melanoma mouse model, OMV@PPA/Zeb substantially suppressed tumor growth without noticeable systemic toxicity. Moreover, OMV@PPA/Zeb significantly promoted the infiltration and activation of CD8 + T cells while reducing regulatory T cells (Tregs) within the tumor microenvironment. The potent antitumor immune response elicited by this platform contributed to its enhanced therapeutic efficacy against melanoma. Overall, this study provides a modular OMV-based strategy for combination immunotherapy in advanced tumors.

Introduction:
Melanoma is one of the most aggressive skin malignancies and remains a major clinical challenge due to its high metastatic potential, heterogeneous antigenic landscape, and immune escape mechanisms ( 1 ). Immune checkpoint inhibitors, especially antibodies targeting the PD-1/PD-L1 axis, have substantially improved the therapeutic outcome of advanced melanoma ( 2 ). Despite the great clinical success, a substantial proportion of patients either fail to respond initially or eventually acquire resistance ( 3 ). The…

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