Engineered Cellular Vesicles Displaying Glycosylated Nanobodies for Cancer Immunotherapy

Immune checkpoint blockade targeting the CD47/SIRPα axis represents an alluring avenue for cancer immunotherapy. However, the compromised efficacy and safety concerns in vivo of conventional anti-CD47 antibodies impede their wide clinical applications. Here we introduced a single type of high-mannose glycans into the nanobody against CD47 (HM-nCD47) and subsequently displayed HM-nCD47 on cellular vesicles (CVs) for enhanced cancer immunotherapy. In this platform, the CVs significantly improved the circulation time of HM-nCD47-CVs, the nCD47 enabled the blockade of the CD47/SIRPα axis, and the HM enhanced recognition of mannose-binding lectin, all synergistically activating the macrophage-mediated antitumor immunity. In both subcutaneous and metastatic murine tumor models, the HM-nCD47-CVs possessed significantly extended half-lives and increased accumulation at the tumor site, resulting in a remarkable macrophage-dependent inhibition of tumor growth, a transcriptomic remodeling of the immune response, and an increase in survival time. By integrating the chemical biology toolbox with cell membrane nanotechnology, the HM-nCD47-CVs represent a new immunotherapeutic platform for cancer and other diseases.