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

Xiaorui Geng1, Silan Liu1,2,3, Yuanwei Pan1

  • 1Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen 518132, China.

Insights

This study introduces fusion nanovesicles (FNVs) that degrade the tumor glycocalyx, enhancing cancer immunotherapy efficacy. These StcE-nCD47-FNVs improve tumor targeting and reduce toxicity for better immune responses.

Area of Science:

  • Biotechnology
  • Immunology
  • Nanomedicine

Background:

  • The tumor glycocalyx shields tumors from immunotherapy by masking checkpoint proteins.
  • Bacterial protease StcE degrades the glycocalyx but has toxicity and immunogenicity issues.
  • Existing immunotherapies face challenges due to the protective tumor microenvironment.

Purpose of the Study:

  • To develop a novel biomimetic platform for targeted glycocalyx degradation and enhanced cancer immunotherapy.
  • To overcome the limitations of free StcE by creating a safer and more effective delivery system.
  • To investigate the therapeutic potential of StcE-nCD47-FNVs in preclinical cancer models.

Main Methods:

  • Engineered cell membrane fusion nanovesicles (FNVs) to co-display StcE and CD47 nanobodies (nCD47) using the SpyTag/SpyCatcher system.
  • Characterized the physicochemical properties and mucin-hydrolyzing activity of the resulting StcE-nCD47-FNVs.
  • Evaluated the efficacy of StcE-nCD47-FNVs in murine models of colorectal and breast cancer, assessing tumor growth, metastasis, and immune cell infiltration.

Main Results:

  • StcE-nCD47-FNVs demonstrated potent mucin degradation and enhanced nCD47 binding to tumor cells.
  • The FNV platform exhibited prolonged circulation, improved tumor accumulation, and better biosafety compared to free StcE.
  • Significant suppression of tumor growth and metastasis was observed, accompanied by M1 macrophage polarization and increased CD8+ T cell infiltration.

Conclusions:

  • StcE-nCD47-FNVs represent a safe, robust, and versatile strategy for breaching the tumor glycocalyx.
  • This integrated approach of glycocalyx engineering and vesicle nanotechnology enhances checkpoint blockade immunotherapy.
  • The developed platform holds promise for next-generation cancer immunotherapies by remodeling the tumor microenvironment.