Immunological Conversion of Solid Tumors Using an Outer Membrane Vesicle Based Checkpoint Nanoinhibitor for Cancer...

Immune checkpoint blockade therapy has achieved clinical success, yet its efficacy is often limited by a dysfunctional tumor microenvironment. Crucially, the impairment of local innate immune cells directly drives the paucity and dysfunctionality of tumor-specific T cells. To address these issues, this study developed a nanoscale immune checkpoint modulator based on bacterial outer membrane vesicles (OMVs), in which a PD-L1 blockade peptide ^DPPA-1 is conjugated onto the OMV surface (OMV-^DPPA-1), with the outer surface coated with a polyethylene glycol (PEG) layer containing a legumain-responsive substrate to form PEG-OMV-^DPPA-1. The modification of PEG not only effectively reduces the immunogenicity of OMV-^DPPA-1, thereby bolstering the safety profile of its intravenous deployment and enhancing tumor targeting, but also enables enzyme-triggered controlled release of OMV-^DPPA-1. In tumor-bearing mice, PEG-OMV-^DPPA-1 not only recruits innate immune cells to alleviate the tumor immune-suppressive microenvironment, transforming immunologically "cold" tumors into "hot" tumors, but also precisely blocks immune checkpoints in the tumor microenvironment, protecting tumor-infiltrating T cells from exhausting. In conclusion, this work illuminates the vast potential of OMVs as an effective immunomodulator that can comprehensively regulate the tumor immune microenvironment to enhance cancer immunotherapy.