Inflammation-targeted nanomedicine prevents tumor metastasis following photodynamic therapy by reversing epithelial-mesenchymal transition and ROS-mediated immunosuppression.

BACKGROUND: Prolonging the duration of photodynamic therapy (PDT) enhances the level of reactive oxygen species (ROS), thereby facilitating tumor ablation. However, our findings indicated that excessive ROS not only induces epithelial-mesenchymal transition (EMT) but also creates an immunosuppressive microenvironment in tumor, thereby triggering tumor metastasis. METHODS: We initially developed neutrophil membrane hybrid liposomes (NLs) that can specifically target inflamed tumor tissues following PDT. Then, we utilized NLs to encapsulate the antioxidant nanozyme FeGA and the antiplatelet drug Lysine Acetylsalicylate (LAS), resulting in the formulation NLASF. RESULTS: Experimental results demonstrated that FeGA effectively scavenges ROS, thereby reversing the immunosuppressive microenvironment induced by prolonged PDT. Furthermore, the incorporation of LAS effectively disrupts the interaction between tumor cells and platelets, mitigating tumor EMT and inhibiting hematogenous tumor metastasis. In a breast cancer mouse model, we observed that treatment with NLASF led to a near-complete suppression of tumor lung metastasis following the prolonged PDT. Additionally, the in vivo application of NLASF did not result in any blood toxicity or organ toxicity, highlighting its significant advantages over the free drugs group. CONCLUSIONS: This study provides a novel approach to enhance the efficacy of PDT and successfully suppress PDT-mediated tumor metastasis.