Ultrahigh Enzyme Loading Metal-Organic Frameworks For Tumor Photo-Immunotherapy

Metal-organic frameworks(MOFs)are considered as promising drug carriers due to their various types,ultra-high porosity,biodegradability,ease of functionalization and adjustability,and have been gained great attention in the treatment of cancer.However,some inherent risk factors such as the high concentration of metal ions,the potential toxicity of organic ligands and organic solvents involved in the preparation process limit MOFs clinical appilication.Also,there are a series of physiological barriers in the delivery process of nanoparticles,which seriously hinder the transportation of drugs and weaken the therapeutic effect.Here,we developed a metal-organic frameworks loaded with collagenase(MOFCol)through a one-step sysnthesis.During green fabrication of MOFCol without an organic solvent,low content of Zn(Ⅱ)was mixed with collagenase and the histidine residues in collagenase were coordinated with Zn(Ⅱ).Then,2-dimethylimidazole was added and joined with the node combining Zn(Ⅱ)and histidine residues to prepare MOFCol.Thus,MOFCol demonstrated ultrahigh encapsulation efficiency(-80 wt%)and low content of metal ions,which endowed MOFCol with lower toxicity than the zeolitic imidazolate framework-8(ZIF-8)biomineralization collagenase.And MOFCol could release collagenase with high enzymatic activity in response to the tumor microenvironment acidity.Collagen is the major component of extracellular matrix(ECM)and plays a critical role in mainting tumor integrity,blocking drug penetration and weakening immune cell infiltration.MOFCol was injected intravenously into tumor bearing mice to deliver collagenase to tumor,inducing collagen degration in ECM.Meanwhile,with the degradation of collagen,the effect of ECM as a barrier was weakened,neovascularization was significantly increased and the penetration of nanoparticles and infiltration of immune cells in tumor were enhanced.Near-infrared-Ⅱ photosensitizer FD1080 was loaded onto MOFCol to form MOFCol/FD that induced immunogenic death of tumor cells in vitro through photothermal therapy.Then,immunogenic dead cells was used as vaccines.It was proved that photothermal therapy-induced immunogenic death of tumor cells can promote the invasion of immune cells in tumor tissues and inhibit tumor growth.Finally,MOFCol/FD combined with anti-PD-1 antibody showed a great therapeutic effect in the treatment of tumorbearing mouse model.