Ultrahigh Enzyme Loading Metal–Organic Frameworks for Deep Tissue Pancreatic Cancer Photoimmunotherapy

Abstract Protein drugs hold promise in treating multiple complex diseases, including cancer. The priority of protein drug application is precise delivery of substantial bioactive protein into tumor site. Metal–organic‐framework (MOF) is widely considered as a promising carrier to encapsulate protein drug owing to the noncovalent interaction between carrier and protein. However, limited loading efficiency and potential toxicity of metal ion in MOF restrict its application in clinical research. Herein, a tumor targeted collagenase‐encapsulating MOF via protein‐metal ion‐organic ligand coordination (PMO Col ) for refining deep tissue pancreatic cancer photoimmunotherapy is developed. By an expedient method in which the ratio of metal ion, histidine residues of protein and ligand is precisely controlled, PMO Col is constructed with ultrahigh encapsulation efficiency (80.3 wt%) and can release collagenase with high enzymatic activity for tumor extracellular matrix (ECM) regulation after reaching tumor microenvironment (TME). Moreover, PMO col exhibits intensively poorer toxicity than the zeolitic imidazolate framework‐8 biomineralized protein. After treatment, the pancreatic tumor with abundant ECM shows enhanced immunocyte infiltration owing to extracellular matrix degradation that improves suppressive TME. By integrating hyperthermia agent with strong near‐infrared absorption (1064 nm), PMO Col can induce acute immunogenicity to host immunity activation and systemic immune memory production to prevent tumor development and recurrence.