Abstract

The tumor glycocalyx forms a protective shield that masks checkpoint proteins and compromises the efficacy of immunotherapies. While the bacterial protease StcE can degrade this barrier by cleaving O-glycosylated mucin domains, its therapeutic potential is hindered by off-target toxicity and high immunogenicity. To overcome these limitations, we developed a biomimetic platform of cell membrane fusion nanovesicles (FNVs) that codisplay StcE and CD47 nanobodies (nCD47) for spatially controlled glycocalyx degradation and enhanced checkpoint blockade. Using the SpyTag/SpyCatcher system, we generated StcE-displaying NVs, which were then fused with nCD47-displaying NVs. The resulting StcE-nCD47-FNVs retained potent mucin-hydrolyzing activity and exhibited well-defined physicochemical properties. By removing the mucin barrier, StcE-nCD47-FNVs significantly enhanced nCD47 binding to CD47 on tumor cells, thereby potentiating antitumor immune responses. More importantly, benefiting from prolonged circulation of FNVs and tumor targeting of nCD47, the StcE-nCD47-FNV platform demonstrated superior tumor accumulation and biosafety compared to free StcE. In murine models of colorectal and breast cancer, StcE-nCD47-FNVs significantly suppressed tumor growth and metastasis by remodeling the tumor microenvironment, as evidenced by increased M1 macrophage polarization and CD8+ T cell infiltration. By integrating glycocalyx engineering with vesicle nanotechnology, StcE-nCD47-FNVs offer a safe, robust, and versatile strategy to breach the tumor glycocalyx for next-generation cancer immunotherapy.

Title

Mucinase-engineered cell membrane nanovesicles degrade the glycocalyx shield to potentiate antitumor immunity

Authors

Xiaorui Geng, Silan Liu, Yuanwei Pan, Lang Rao 

Journal Information

Proceedings of the National Academy of Sciences of the United States of America (2026)

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