“Three-birds-one-stone” environment responsive delivery system with tumor microenvironment remodeling to enhance solid tumor therapy

Unique tumor microenvironment (TME), tumor cell reprogramming and tumor tissues wrapped by rigid extracellular matrix (ECM), these natural physiological barriers can compromise solid tumor treatment. In this study, we constructed a “three-birds-one-stone” delivery system (PEG-MnO2/ZIF/DOX&NK@LAC) with environment responsive behavior, which can effectively overcome the natural physical barrier of solid tumor to reshape TME. The obtained MnO2 shell not only endows PEG-MnO2/ZIF/DOX&NK@LAC with near-infrared response performance that can induce tumor cells apoptosis to release tumor-associated antigens under near-infrared light (NIR) irradiation, but also can undergo Fenton reaction with H2O2 to alleviate hypoxia TME while generate a large number of hydroxyl radicals. Importantly, PEG-MnO2/ZIF/DOX&NK@LAC contained manganese ions can effectively activate cGAS-STING pathway, thereby activating body’s anti-tumor immunity. Subsequently, MnO2/ZIF/DOX&NK modified into Lactobacillus surface via Lactobacillus can colonize and survive in an anaerobic environment to help MnO2/ZIF/DOX&NK tumor tissues precising delivery. Then, the acidic TME can collapse the framework of MnO2/ZIF/DOX&NK in PEG-MnO2/ZIF/DOX&NK@LAC to realize NK and DOX controllable releasing. The released NK can inhibit the fibrosis of tumor-associated fibroblasts and degrade ECM components to reduce the hardness of tumor tissues, and further promotes DOX infiltration within tumor tissues, thereby achieving the cascade effect in tumor treatment.