Nattokinase-mediated regulation of tumor physical microenvironment to enhance the therapeutic effect of photosensitive in situ gel vaccine for tumor synergistic therapy

Tumor vaccine utilizes tumor cells or tumor antigen to induce anti-tumor immune response to inhibit tumor growth. However, due to the heterogeneity of tumor tissues and their being surrounded by dense extracellular matrix, the therapeutic effect of tumor vaccines is compromised. In this study, we used folic acid-modified doxorubicin-loaded polyserotonin nanoparticles (FA-PPLT@DOX NAs) cross-linked with phenylboronic hyaluronic acid to prepare environmental-responsive in situ photosensitive gel vaccine (FPLT@DOX PA). Once FPLT@DOX PA exposed under near infrared light irradiation, which can induce tumor cell apoptosis, released tumor-related antigen and effectively solved tumor heterogeneity and forms an “antigen library” in tumor lesions to sustain released tumor antigen. Subsequently, unique tumor microenvironment degraded FPLT@DOX PA and released cross-linked FA-PPLT@DOX NAs. Then, the folate molecules modified by FA-PPLT@DOX NAs combines with folate receptors on tumor cells surface to enhance tumor cells’ phagocytosis. To enhance the infiltration of immune cells and FA-PPLT@DOX NAs in tumor tissues, we injected nattokinase into solid tumor tissues before treatment. This strategy can not only degrade the extracellular matrix, but also inhibit the fibrosis of tumor-related fibroblasts, thereby reducing tumor hardness to enhance drugs intra-tumor perfusion. The result shown that this three-mode combined treatment strategy can not only effectively compensate the shortcome of each single treatment, but also induce long-term immune memory effect to inhibit tumor recurrence and metastasis. In this study, the positive regulation of tumor microenvironment-immune circulation was realized through the temporal and spatial coordination of photothermal ablation, chemotherapy and immune regulation, which provided a new treatment concept for the bottleneck of solid tumor treatment.