Nanoscale Metal-Organic Layers for Biomedical Applications

As a monolayer version of nanoscale metal organic frameworks (nMOFs), nanoscale metal-organic layers (nMOLs) have recently emerged as a novel class of two-dimensional (2D) molecular nanomaterials. nMOLs are built from metal-oxo secondary building units (SBUs) with suitable coordination modes and organic linkers with proper geometries in a bottom-up fashion by carefully controlling the reaction temperature, capping agents, water concentration, and other parameters. M-6-BTB and related nMOLs are formed by linking M-6(mu(3)-O)(4)(mu(3)-OH)(4) (M = Zr4+, Hf4+, Ce4+) SBUs and planar tricarboxylate bridging ligands such as 1,3,5-benzene-tribenzoate (BTB), while M-12-nMOLs are constructed from M-12(mu(3)-O)(8)(mu(3)-OH)(8) (mu(2)-OH)(6) (M = Zr4+, Hf4+) SBUs and linear dicarboxylate ligands such as 5,15-di(p-benzoato)porphyrin (DBP). Mechanistic studies revealed the important roles of capping agents and water on the growth of nMOLs and the stepwise growth process involving the partial hydrolysis of metal ions to form metal-oxo clusters with capping agents and the subsequent replacement of capping agents by bridging ligands. The 2D nature of nMOLs facilitates the postsynthetic modification of bridging ligands and the exchange of capping agents to simultaneously incorporate multifunctionalities into nMOLs. In this Account, we discuss the design principles, growth mechanisms, and postsynthetic functionalization strategies for nMOLs and summarize our research efforts to design nMOLs for various biological and biomedical applications. We first outline the strategies for the design and synthesis of M-6- and M-12-nMOLs via a dimensional reduction strategy and discuss the growth mechanisms of nMOLs. We then highlight the methods for the postsynthetic functionalization of nMOLs. We demonstrate the application of nMOLs in two broad categories. We first show the design and development of nMOLs for radiotherapy-radiodynamic therapy (RT-RDT) and further combination with checkpoint blockade immunotherapy. The evolution of Hf-6-nMOLs to Hf-12-nMOLs illustrates the control of nMOL morphology and photosensitizer loading for optimal RT-RDT effects. The nMOL-mediated RT-RDT is further combined with checkpoint blockade cancer immunotherapy to enable the treatment of systemic diseases via local X-ray irradiation. We next demonstrate nMOLs as a versatile platform for ratiometric sensing/imaging and drug delivery. The easily accessible sites on SBUs and ligands in nMOLs provide conjugation sites for multifunctional sensors and drugs, allowing for simultaneous ratiometric sensing of the pH and oxygen concentration or pH and glutathione concentration in mitochondria as well as highly effective photodynamic therapy with insoluble conjugated zinc phthalocyanine. We discuss the limitations of currently available nMOLs in terms of a lack of structural diversity and lower stability compared to nMOFs. We also point out the untapped potential of using the inherent hierarchy of SBU and bridging ligand structures to integrate multiple functionalities for synergistic functions. With the establishment of general design principles and an understanding of nMOL growth mechanisms, we believe that nMOLs will emerge as a fertile research field with great potential for applications beyond radiotherapy-radiodynamic therapy, immunotherapy, multifunctional biosensing, and drug delivery.