Abstract

Natural killer (NK) cell-based cancer immunotherapy, which exhibits anti-tumor activity independent of the major histocompatibility complex (MHC), has emerged as a highly promising anti-cancer strategy. However, the low concentration of NK cells in tumor regions, severe functional impairment, and immunosuppression have considerably restricted the successful clinical implementation of NK cells-based cancer immunotherapy. Here, we introduce DBEP@αMV, a self-assembled nanomedicine encapsulated in bioengineered vesicles. DBEP contains a mitochondria-targeting two-photon photosensitizer and indomethacin, while αMV incorporates a CD47 blocker, MMP2-cleavable peptide, and VSV-G fusion protein. Within the MMP2-rich tumor microenvironment releases the CD47 blocker, followed by intracellular disintegration after endocytosis of the nanomedicine. The inhibition of CD47 and PGE2 enhanced NK cell enrichment and cytotoxicity. Two-photon photodynamic therapy (PDT) triggers mitochondrial apoptosis (mtApoptosis) in tumor cells, directly killing cancer cells and enhancing the vulnerability of residual tumor cells to NK cells. Additionally, enriched NK cells recruit DCs and T cells, reshaping the tumor immune microenvironment. This study presents a novel strategy for enhancing NK cells-based immunotherapy and offers a promising direction for cancer nano-immunotherapy.

文章链接：https://doi.org/10.1016/j.cej.2025.167868