Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy

The low immunogenicity of tumors remains one of the major limitations of cancer immunotherapy.Herein,we report a bacterial metabolisminitiated and photothermal-enhanced nanocatalytic therapy strategy to completely eradicate primary tumor by triggering highly effective antitumor immune responses.Briefly,a microbiotic nanomedicine,designated as Cu_(2)O@ΔSt,has been constructed by conjugating PEGylated Cu_(2)O nanoparticles on the surface of an engineered Salmonella typhimurium strain(ΔSt).Owing to the natural hypoxia tropism ofΔSt,Cu_(2)O@ΔSt could selectively colonize hypoxic solid tumors,thus minimizing the adverse effects of the bacteria on normal tis-sues.Upon bacterial metabolism within the tumor,Cu_(2)O@ΔSt generates H_(2)S gas and other acidic substances in the tumor microenvironment(TME),which will in situ trigger the sulfidation of Cu_(2)O to form CuS facilitating tumor-specific photothermal therapy(PTT)under local NIR laser irradiation on the one hand.Meanwhile,the dissolved Cu+ions from Cu_(2)O into the acidified TME enables the nanocatalytic tumor therapy by catalyzing the Fenton-like reaction of decom-posing endogenous H_(2)O_(2) into cytotoxic hydroxyl radicals(·OH)on the other hand.Such a bacterial metabolism-triggered PTT-enhanced nanocatalytic treatment could effectively destroy tumor cells and induce a massive release of tumor antigens and damage-associated molecular patterns,thereby sensitizing tumors to checkpoint blockade(ICB)therapy.The combined nanocatalytic and ICB therapy results in the much-inhibited growth of distant and metastatic tumors,and more importantly,induces a powerful immunological memory effect after the primary tumor ablation.

Starvation-Sensitized and Oxygenation-Promoted Tumor Sonodynamic Therapy by a Cascade Enzymatic Approach

The therapeutic outcomes of noninvasive sonodynamic therapy(SDT)are always compromised by tumor hypoxia,as well as inherent protective mechanisms of tumor.Herein,we report a simple cascade enzymatic approach of the concurrent glucose depletion and intratumoral oxygenation for starvation-sensitized and oxygenation-amplified sonodynamic therapy using a dual enzyme and sonosensitizer-loaded nanomedicine designated as GOD/CAT@ZPF-Lips.In particular,glucose oxidase-(GOD-)catalyzed glycolysis would cut off glucose supply within the tumor,resulting in the production of tumor hydrogen peroxide(H_(2)O_(2))while causing tumor cells starvation.The generated H_(2)O_(2)could subsequently be decomposed by catalase(CAT)to generate oxygen,which acts as reactants for the abundant singlet oxygen(^(1 O_(2))production by loaded sonosensitizer hematoporphyrin monomethyl ether(HMME)upon the US irradiation,performing largely elevated therapeutic outcomes of SDT.In the meantime,the severe energy deprivation enabled by GOD-catalyzed glucose depletion would prevent tumor cells from executing protective mechanisms to defend themselves and make the tumor cells sensitized and succumbed to the cytotoxicity of^(1 O_(2)).Eventually,GOD/CAT@ZPF-Lips demonstrate the excellent tumoral therapeutic effect of SDT in vivo without significant side effect through the cascade enzymatic starvation and oxygenation,and encouragingly,the tumor xenografts have been found completely eradicated in around 4 days by the intravenous injection of the nanomedicine without reoccurrence for as long as 20 days.

Nanomaterials-Based Tumor Microenvironment Modulation for Magnifying Sonodynamic Therapy

CONSPECTUS:Sonodynamic therapy(SDT)is a noninvasive and more preferable therapeutic modality than photodynamic therapy(PDT)due to deeper tissue penetration,which utilizes sonosensitizers to produce reactive oxygen species(ROS)to kill tumor cells and arouse immune responses.However,it still suffers from low ROS production efficiency and insufficient systematic immune activation,which thus has attracted increasing attention and researchers to engage in this field.