Metal organic frameworks based intelligent nanoadjuvants for boosting tumor immunotherapy through enhanced ICD and lactic acid regulation

Abstract

Immunotherapy has been considered as a potent antitumor modality while its efficacy is frequently hampered by the insufficient immunogenicity and immunosuppressive tumor microenvironment (TME) with overexpressed lactic acid (LA). Herein, an intelligent nanoadjuvant MOF@LOD-siRNA@Lips-FA (MLSLF) was developed by loading lactate oxidase (LOD) and monocarboxylate transporter 4 (MCT4)-inhibiting siRNA into Fe-MOF and further coated with folate-liposomes (FA-lip) for enhanced immunotherapy. The MLSLF could response to endogenous glutathione (GSH), resulting in the depletion of GSH and production of •OH for effective chemodynamic therapy (CDT). On one hand, the death of cancer cells would arouse immunogenic cell death (ICD) to release antigens and enhance tumor immunogenicity. Meanwhile, LOD could decompose intracellular LA to H2O2, which could further promote ICD and boost anti-tumor immune response. On the other hand, the siRNA could restrict the expression of MCT4, which would hinder the intracellular LA efflux. The combination of LOD and siRNA could reduce the LA content in TME and relieve immunosuppression TME. The in vivo results revealed that MLSLF could effectually suppress the growth of primary and distant tumors in tumor-bearing mice. Therefore, the smart MLSLF could be a synergistic anti-tumor strategy for efficient immunotherapy through the combination of enhanced ICD and LA metabolism blockade.