Nanovesicle-Mediated Targeted Delivery of Immune Checkpoint Blockades to Potentiate Therapeutic Efficacy and Prevent Side Effects.

Despite the clinically proven efficacies of immune checkpoint blockades, including anti-cytotoxic T lymphocyte-associated protein 4 antibody (αCTLA-4), the low response rate and immune-related adverse events (irAEs) in cancer patients represent major drawbacks of the therapy. These drawbacks of αCTLA-4 therapy are mainly due to the suboptimal activation of tumor-specific cytotoxic T lymphocytes (CTLs) and the systemic nonspecific activation of T cells. To overcome such drawbacks, αCTLA-4 is delivered by dendritic cell-derived nanovesicles presenting tumor antigens (DCNV-TAs) that exclusively interact with tumor-specific T cells, leading to selective activation of tumor-specific CTLs. Compared to conventional αCTLA-4 therapy, treatment with αCTLA-4-conjugated DCNV-TAs significantly inhibits tumor growth and reduces irAEs in syngeneic tumor-bearing mice. This study demonstrates that the spatiotemporal presentation of both αCTLA-4 and tumor antigens enables selective activation of tumor-specific T cells and potentiates the antitumor efficacy of αCTLA-4 without inducing systemic irAEs.