Developing novel drug carriers for pulmonary delivery is necessary to achieve higher efficacy and consistency for treating pulmonary diseases while limiting off-target side effects that occur from alternative routes of administration. Metal–organic frameworks (MOFs) have recently emerged as a class of materials with characteristics well-suited for pulmonary drug delivery, with chemical tunability, high surface area, and pore size, which will allow for efficient loading of therapeutic cargo and deep lung penetration. UiO-66, a zirconium and terephthalic acid-based MOF, has displayed notable chemical and physical stability and potential biocompatibility; however, its feasibility for use as a pulmonary drug delivery vehicle has yet to be examined. Here, we evaluate the use of UiO-66 nanoparticles (NPs) as novel pulmonary drug delivery vehicles and assess the role of missing linker defects in their utility for this application. We determined that missing linker defects result in differences in NP aerodynamics but have minimal effects on the loading of model and therapeutic cargo, cargo release, biocompatibility, or biodistribution. This is a critical result, as it indicates the robust consistency of UiO-66, a critical feature for pulmonary drug delivery, which is plagued by inconsistent dosage because of variable properties. Not only that, but UiO-66 NPs also demonstrate pH-dependent stability, with resistance to degradation in extracellular conditions and breakdown in intracellular environments. Furthermore, the carriers exhibit high biocompatibility and low cytotoxicity in vitro and are well-tolerated in in vivo murine evaluations of orotracheally administered NPs. Following pulmonary delivery, UiO-66 NPs remain localized to the lungs before clearance over the course of seven days. Our results demonstrate the feasibility of using UiO-66 NPs as a novel platform for pulmonary drug delivery through their tunable NP properties, which allow for controlled aerodynamics and internalization-dependent cargo release while displaying remarkable pulmonary biocompatibility.

UiO-66, a zirconium(IV) metal−organic framework composed of six-metal clusters and terephthalic acid ligands, displays excellent thermal and chemical stability and has functions in gas storage, catalysis, selective adsorption, and drug delivery. Though the stability of UiO-66 is highly advantageous, simultaneous synthetic control over particle size and defectiveness of UiO-66 remains difficult to attain. Using an acid-free solvothermal synthesis, we demonstrate that particle size, defectiveness, and inherent fluorescence of UiO-66 can be precisely tuned using the molar ligand-to-metal ratio, quantified water content, and reaction time during synthesis. These three synthetic handles allow for reproducible modulation of UiO-66 defectiveness between 0 and 12% and particle size between 20 and 120 nm, while maintaining high crystallinity in the nanoparticles that were formed. We also find that particle defectiveness is linked to common overestimation of particle size measurements obtained via dynamic light scattering and propose a model to correct elevated hydrodynamic diameter measurements. Finally, we report inherent fluorescence of nonfunctionalized UiO-66, which exhibits peak fluorescence at a wavelength of 390 nm following excitation at 280 nm and is maximized in large, defect-free particles. Overall, this synthetic approach and characterization of defect, size, and fluorescence represent new opportunities to tune the physiochemical properties of UiO-66.

Metal–organic frameworks and porous coordination cages have shown incredible promise as a result of their high tunability. However, syntheses pursuing precisely targeted mixed functionalities, such as multiple ligand types or mixed-metal compositions are often serendipitous, require postsynthetic modification strategies, or are based on complex ligand design. Herein, we present a new method for the controlled synthesis of mixed functionality metal–organic materials via the preparation of porous salts. More specifically, the combination of porous ionic molecules of opposite charge affords framework-like materials where the ratio between cationic cage and anionic cage is potentially tunable. The resulting doubly porous salt displays the spectroscopic signatures of the parent cages with increased gas uptake capacities as compared to starting materials. This approach will be widely applicable to all families of porous ions and represents a new and powerful method for the synthesis of porous solids with tailored functionalities.

Zirconium-based coordination cages have received considerable recent attention as a result of their structural tunability and amenability to postsynthetic modification. Although these structures have adopted tetrahedral (4-vertex) or cigar (2-vertex) geometries depending on the shape and nuclearity of the ligand used in their assembly, their structures have not previously been shown to be either tunable or dynamic. Here, we examine the speciation of a series of zirconium-based cages where the geometry and nuclearity of the product cage can be tuned via judicious functionalization of dicarboxylate ligands. We further show that many of these materials exist as both cage structures in solution or the solid state. With appropriate solvent exchange and activation conditions, the cigar structures can display Brunauer–Emmett–Teller (BET) surface areas as high as 123 m2/g. As a result of their expanded pore structures, the tetrahedra display significantly increased BET surface areas approaching 700 m2/g. These results show that by appropriate ligand functionalization the structures of zirconium-based cages can be modified to tune their phase and surface area. Finally, the isolation of phase-pure cages allows for the utilization of anion metathesis reactions to tune their solubility.

The electrochemical synthesis of metal–organic frameworks (MOFs) has been widely explored but has involved indirect routes, including anodic dissolution of solid metal electrodes or the use of interfacial redox chemistry to generate base equivalents and drive MOF assembly. These methods are limited in scope, as the former relies on the use of an anode consisting of the metal ion to be incorporated into the MOF, and the latter relies on the compatibility of the metal/ligand solution with the probase that is subsequently oxidized or reduced. We report the facile, direct electrochemical syntheses of four iron-based MOFs via controlled potential oxidation of dissolved metal cations. Oxidation of Fe(II) at +0.75 V (vs Ag/Ag + ) in a solution containing 2,6-lutidine and terephthalic acid affords highly crystalline Fe-MIL-101. Controlled potential electrolysis with carboxy-functionalized ITO affords Fe-MIL-101 grown directly on the surface of modified electrodes. The methods we report herein represent the first general routes that employ interfacial electrochemistry to alter the oxidation state of metal ions dissolved in solution to directly trigger MOF formation. The reported method is functional group tolerant and will be broadly applicable to the bulk synthesis or surface growth of a range of MOFs based on metal ions with accessible oxidation states.