Genetically Engineering Cell Membrane‐Coated BTO Nanoparticles for MMP2‐Activated Piezocatalysis‐Immunotherapy

Abstract Tumor immunotherapy based on immune checkpoint blockade (ICB) still suffers from low host response rate and non‐specific distribution of immune checkpoint inhibitors, greatly compromising the therapeutic efficiency. Herein, cellular membrane stably expressing matrix metallopeptidase 2 (MMP2)‐activated PD‐L1 blockades is engineered to coat ultrasmall barium titanate (BTO) nanoparticle for overcoming the immunosuppressive microenvironment of tumors. The resulting M@BTO NPs can significantly promote the BTO's tumor accumulation, while the masking domains on membrane PD‐L1 antibodies are cleaved when exposure to MMP2 highly expressed in tumor. With ultrasound (US) irradiation, M@BTO NPs can simultaneously generate reactive oxygen species (ROS) and O₂ based on BTO mediated piezocatalysis and water splitting, significantly promoting the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and improving the PD‐L1 blockade therapy to the tumor, resulting in effective tumor growth inhibition and lung metastasis suppression in a melanoma mouse model. This nanoplatform combines MMP2‐activated genetic editing cell membrane with US responsive BTO for both immune stimulation and specific PD‐L1 inhibition, providing a safe and robust strategy in enhancing immune response against tumor.