In past decades, regular porous architectures have received a great amount of attention because of their versatile functions and applications derived from their efficient adsorption of various guests. However, most reported porous architectures exist only in the solid state. Therefore, their applications as
biomaterials may face several challenges, such as phase separation, slow degradation, and long-term accumulation in the body. This Account summarizes our efforts with respect to the development and biomedical applications of water-soluble 3D diamondoid supramolecular organic frameworks (dSOFs), a family of supramolecular
polymers that possess intrinsic regular nanoscale porosity.dSOFs have been constructed from tetratopic components and
cucurbit[8]uril (CB[8]) through hydrophobically driven encapsulation by CB[8] for intermolecular dimers formed by peripheral aromatic subunits of the tetratopic components in water. All dSOFs exhibit porosity regularity or periodicity in aqueous
solution, which is confirmed by
solution-phase
synchrotron SAXS and XRD experiments. Dynamic light scattering (DLS) reveals that their sizes range from 50 to 150 nm, depending on the concentrations of the components. As nonequilibrium supramolecular architectures, dSOFs can maintain their nanoscale sizes at micromolar concentrations for dozens of hours. Their diamondoid pores have aperture sizes ranging from 2.1 to 3.6 nm, whereas their water solubility and porosity regularity allow them to rapidly include discrete guests driven by ion-pair electrostatic attraction, hydrophobicity, or a combination of the two interactions. The guests may be small molecule or large macromolecular drugs, photodynamic agents (PDAs), or
DNA.The rapid inclusion of bioactive guests into dSOFs has led to two important biofunctions. The first is to function as antidotes through including residual drugs. For heparins, the inclusion results in full neutralization of their
anticoagulant activity. For clinically used
porphyrin PDAs, the inclusion can alleviate their long-term posttreatment
phototoxicity but does not reduce their photodynamic efficacy. The second is to function as in situ loading carriers for the intracellular delivery of
antitumor drugs or
DNA. Their nanoscale sizes bring out their ability to overcome the multidrug resistance of
tumor cells, which leads to a remarkable enhancement of the bioactivity of the included drugs. By conjugating
aldoxorubicin to tetrahedral components,
albumin-mimicking
prodrugs have also been constructed, which conspicuously improves the efficacy of
aldoxorubicin toward multi-
drug-resistant
tumors through the delivery of the frameworks. As new supramolecular drugs and carriers, dSOFs are generally biocompatible. Thus, further efforts might lead to medical benefits in the future.