Engineered hybrid cell membrane nanovesicles for potentiated cancer immunotherapy through dual immune checkpoint inhibition†

Abstract

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable success in treating various types of solid tumors; however, only a limited number of patients currently benefit from these therapeutic agents. Developing novel ICIs that elicit systemic and durable antitumor immune responses remains a significant challenge in improving immunotherapy outcomes. In this study, we engineered PD-1/LAG-3 receptors onto cell membrane nanovesicles to simultaneously block two immune checkpoints for the treatment of colorectal cancer. This dual-checkpoint blockade strategy led to significantly more potent tumor growth suppression in mice with MC38 xenografts compared to nanovesicles targeting PD-1 or LAG-3 alone. Notably, the hybrid nanovesicles substantially rejuvenated exhausted CD8⁺ T cells, promoting dendritic cell maturation and depleting regulatory T cells (Tregs). This research highlights the promising potential of cell membrane nanovesicles as an effective platform for delivering multiple immune checkpoints in cancer immunotherapy, offering a novel strategy to enhance therapeutic efficacy.