DNA has proven of high utility to modulate the surface functionality of metal-organic frameworks (MOFs) for various biomedical applications. Nevertheless, current methods for preparing DNA-MOF nanoparticles rely on either inefficient covalent conjugation or specific modification of oligonucleotides. In this work, we report that unmodified oligonucleotides can be loaded on MOFs with high density (∼2500 strands/particle) via intrinsic, multivalent coordination between DNA backbone phosphate and unsaturated zirconium sites on MOFs. More significantly, surface-bound DNA can be efficiently released in either bulk solution or specific organelles in live cells when free phosphate ions are present. As a proof-of-concept for using this novel type of DNA-MOFs in immunotherapy, we prepared a construct of immunostimulatory DNA-MOFs (isMOFs) by intrinsically coordinating cytosine-phosphate-guanosine (CpG) oligonucleotides on biocompatible zirconium MOF nanoparticles, which was further armed by a protection shell of calcium phosphate (CaP) exoskeleton. We demonstrated that isMOFs exhibited high cellular uptake, organelle specificity, and spatiotemporal control of Toll-like receptors (TLR)-triggered immune responses. When isMOF reached endolysosomes via microtubule-mediated trafficking, the CaP exoskeleton dissolved in the acidic environment and in situ generated free phosphate ions. As a result, CpG was released from isMOFs and stimulated potent immunostimulation in living macrophage cells. Compared with naked CpG-MOF, isMOFs exhibited 83-fold up-regulation in stimulated secretion of cytokines. We thus expect this isMOF design with soluble CaP exoskeleton and an embedded sequential "protect-release" program provides a highly generic approach for intracellular delivery of therapeutic nucleic acids.
Owing to unique morphology, ultrasmall lateral sizes, and exceptional properties, graphene quantum dots (GQDs) hold great potential in many applications, especially in the field of electrochemical biosensors, bioimaging, drug delivery, et cetera. Its biosafety and potential cytotoxicity to human and animal cells has been a growing concern in recent years. In this work, the potential cytotoxicity of GQDs was evaluated by molecular dynamics simulations. Our simulation demonstrates that small size GQDs could easily permeate into the lipid membrane in a vertical way. It is relatively difficult to permeate into the lipid membrane for GQDs that are larger than GQD61 on the nanosecond time-scale. The thickness of the POPC membrane could even be affected by the small size of GQDs. Free energy calculations revealed that the free energy barrier of GQD permeation through the lipid membrane could greatly change with the change of GQD size. Under high GQD concentration, the GQD molecules could rapidly aggregate in water but disaggregate after entering into the membrane interior. Moreover, high concentrations of GQDs could induce changes in the structure properties and diffusion properties of the lipid bilayer, and it may affect the cell signal transduction. However, GQDs with relatively small size are not large enough to mechanically damage the lipid membrane. Our results suggest that the cytotoxicity of GQDs with small size is low and may be appropriate for biomedical application.
Metal−organic frameworks (MOFs) are porous crystalline materials with promising applications in molecular adsorption, separation, and catalysis. It has been discovered recently that structural defects introduced unintentionally or by design could have a significant impact on their properties. However, the exact chemical composition and structural evolution under different conditions at the defects are still under debate. In this study, we performed multidimensional solid-state nuclear magnetic resonance (SSNMR) coupled with computer simulations to elucidate an important scenario of MOF defects, uncovering the dynamic interplay between residual acetate and water. Acetate, as a defect modulator, and water, as a byproduct, are prevalent defect-associated species, which are among the key factors determining the reactivity and stability of defects. We discovered that acetate molecules coordinate to a single metal site monodentately and pair with water at the neighboring position. The acetates are highly flexible, which undergo fast libration as well as a slow kinetic exchange with water through dynamic hydrogen bonds. The dynamic processes under variable temperatures and different hydration levels have been quantitatively analyzed across a broad time scale from microseconds to seconds. The integration of SSNMR and computer simulations allows a precision probe into defective MOF structures with intrinsic dynamics and disorder.
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