Metal-Organic Frameworks: Unconventional Nanoweapons against COVID.

The SARS-CoV-2 (COVID-19) pandemic outbreak led to enormous social and economic repercussions worldwide, felt even to this date, making the design of new therapies to combat fast-spreading viruses an imperative task. In the face of this, diverse cutting-edge nanotechnologies have risen as promising tools to treat infectious diseases such as COVID-19, as well as challenging illnesses such as cancer and diabetes. Aside from these applications, nanoscale metal-organic frameworks (nanoMOFs) have attracted much attention as novel efficient drug delivery systems for diverse pathologies. However, their potential as anti-COVID-19 therapeutic agents has not been investigated. Herein, we propose a pioneering anti-COVID MOF approach by studying their potential as safe and intrinsically antiviral agents through screening various nanoMOF. The iron(III)-trimesate MIL-100 showed a noteworthy antiviral effect against SARS-CoV-2 at the micromolar range, ensuring a high biocompatibility profile (90% of viability) in a real infected human cellular scenario. This research effectively paves the way toward novel antiviral therapies based on nanoMOFs, not only against SARS-CoV-2 but also against other challenging infectious and/or pulmonary diseases.

Potential antiprostatic performance of novel lanthanide-complexes based on 5-nitropicolinic acid.

Two new lanthanide-complexes based on the 5-nitropicolinate ligand (5-npic) were obtained and fully characterized. Single-crystal X-ray diffraction revealed that these compounds are isostructural to a Dy-complex, previously published by us, based on dinuclear monomers link together with an extended hydrogen bond network, providing a final chemical formula of [Ln2(5-npic)6(H2O)4]·(H2O)2, where Ln = Dy (1), Gd (2), and Tb (3). Preliminary photoluminescent studies exhibited a ligand-centered emission for all complexes. The potential antitumoral activity of these materials was assayed in a prostatic cancer cell line (PC-3; the 2nd most common male cancerous disease), showing a significant anticancer activity (50-60% at 500 µg·mL-1). In turn, a high biocompatibility by both, the complexes and their precursors in human immunological HL-60 cells, was evidenced. In view of the strongest toxic effect in the tumoral cell line provided by the free 5-npic ligand (~ 40-50%), the overall anticancer complex performance seems to be triggered by the presence of this molecule.

Nanoscaled metal-organic frameworks: charting a transformative path for cancer therapeutics and beyond.

Through this inspirational note, we would like to highlight the potential of nanoscaled metal-organic frameworks within the biomedical field. The unique properties of these materials that make them promising candidates for new nanomedicines are assessed here as well as the progression reached so far for combinational cancer therapies and theranostic, along with its most recent advances in nanomedicine. Finally, the perspective and challenges of these materials within this field is discussed.

Enzyme_Metal-Organic Framework Composites as Novel Approach for Microplastic Degradation.

Plastic pollution is one of the main worldwide environmental concerns. Our lifestyle involves persistent plastic consumption, aggravating the low efficiency of wastewater treatment plants in its removal. Nano/microplastics are accumulated in living beings, pushing to identify new water remediation strategies to avoid their harmful effects. Enzymes (e. g., Candida rugosa-CrL) are known natural plastic degraders as catalysts in depolymerization reactions. However, their practical use is limited by their stability, recyclability, and economical concerns. Here, enzyme immobilization in metal-organic frameworks (CrL_MOFs) is originally presented as a new plastic degradation approach to achieve a boosted plastic decomposition in aqueous systems while allowing the catalyst cyclability. Bis-(hydroxyethyl)terephthalate (BHET) was selected as model substrate for decontamination experiments for being the main polyethylene terephthalate (PET) degradation product. Once in contaminated water, CrL_MOFs can eliminate BHET (37 %, 24 h), following two complementary mechanisms: enzymatic degradation (CrL action) and byproducts adsorption (MOF effect). As a proof-of-concept, the capacity of a selected CrL_MOF composite to eliminate the BHET degradation products and its reusability are also investigated. The potential of these systems is envisioned in terms of improving enzyme cyclability, reducing costs along with feasible co-adsorption of plastic byproducts and other harmful contaminants, to successfully remove them in a single step.

Proving the Antimicrobial Therapeutic Activity on a New Copper-Thiosemicarbazone Complex.

The misuse and overdose of antimicrobial medicines are fostering the emergence of novel drug-resistant pathogens, providing negative repercussions not only on the global healthcare system due to the rise of long-term or chronic patients and inefficient therapies but also on the world trade, productivity, and, in short, to the global economic growth. In view of these scenarios, novel action plans to constrain this antibacterial resistance are needed. Thus, given the proven antiproliferative tumoral and microbial features of thiosemicarbazone (TSCN) ligands, we have here synthesized a novel effective antibacterial copper-thiosemicarbazone complex, demonstrating both its solubility profile and complex stability under physiological conditions, along with their safety and antibacterial activity in contact with human cellular nature and two most predominant bacterial strains, respectively. A significant growth inhibition (17% after 20 h) is evidenced over time, paving the way toward an effective antibacterial therapy based on these copper-TSCN complexes.

Antiadherent AgBDC Metal-Organic Framework Coating for Escherichia coli Biofilm Inhibition.

Surface microbial colonization and its potential biofilm formation are currently a major unsolved problem, causing almost 75% of human infectious diseases. Pathogenic biofilms are capable of surviving high antibiotic doses, resulting in inefficient treatments and, subsequently, raised infection prevalence rates. Antibacterial coatings have become a promising strategy against the biofilm formation in biomedical devices due to their biocidal activity without compromising the bulk material. Here, we propose for the first time a silver-based metal-organic framework (MOF; here denoted AgBDC) showing original antifouling properties able to suppress not only the initial bacterial adhesion, but also the potential surface contamination. Firstly, the AgBDC stability (colloidal, structural and chemical) was confirmed under bacteria culture conditions by using agar diffusion and colony counting assays, evidencing its biocide effect against the challenging E. coli, one of the main representative indicators of Gram-negative resistance bacteria. Then, this material was shaped as homogeneous spin-coated AgBDC thin film, investigating its antifouling and biocide features using a combination of complementary procedures such as colony counting, optical density or confocal scanning microscopy, which allowed to visualize for the first time the biofilm impact generated by MOFs via a specific fluorochrome, calcofluor.

Antibacterial Activity of Two Zn-MOFs Containing a Tricarboxylate Linker.

Metal-organic frameworks (MOFs) can be used as reservoirs of metal ions with relevant antibacterial effects. Here, two novel Zn-based MOFs with the formulas [Zn4(µ4-O)(µ-FA)L2] (GR-MOF-8) and [Zn4(µ4-O)L2(H2O)] (GR-MOF-9) (H3L: 5-((4-carboxyphenyl)ethynyl) in isophthalic acid and FA (formate anion) were solvothermally synthetized and fully characterized. The antibacterial activity of GR-MOF-8 and 9 was investigated against Staphylococcus aureus (SA) and Escherichia Coli (EC) by the agar diffusion method. Both bacteria are among the most relevant human and animal pathogens, causing a wide variety of infections, and are often related with the development of antimicrobial resistances. While both Zn-based materials exhibited antibacterial activity against both strains, GR-MOF-8 showed the highest inhibitory action, likely due to a more progressive Zn release under the tested experimental conditions. This is particularly evidenced in the inhibition of SA, with an increasing effect of GR-MOF-8 with time, which is of great significance to ensure the disappearance of the microorganism.

Copper Glufosinate-Based Metal-Organic Framework as a Novel Multifunctional Agrochemical.

Pesticides are agrochemical compounds used to kill pests (insects, rodents, fungi, or unwanted plants), which are key to meet the world food demand. Regrettably, some important issues associated with their widespread/extensive use (contamination, bioaccumulation, and development of pest resistances) demand a reduction in the amount of pesticide applied in crop protection. Among the novel technologies used to combat the deterioration of our environment, metal-organic frameworks (MOFs) have emerged as innovative and promising materials in agroindustry since they possess several features (high porosity, functionalizable cavities, ecofriendly composition, etc.) that make them excellent candidates for the controlled release of pesticides. Moving toward a sustainable development, in this work, we originally describe the use of pesticides as building blocks for the MOF construction, leading to a new type of agricultural applied MOFs (or AgroMOFs). Particularly, we have prepared a novel 2D-MOF (namely, GR-MOF-7) based on the herbicide glufosinate and the widely used antibacterial and fungicide Cu2+. GR-MOF-7 crystallizes attaining a monoclinic P21/c space group, and the asymmetric unit is composed of one independent Cu2+ ion and one molecule of the Glu2- ligand. Considering the significant antibacterial activity of Cu-based compounds in agriculture, the potential combined bactericidal and herbicidal effect of GR-MOF-7 was investigated. GR-MOF-7 shows an important antibacterial activity against Staphylococcus aureus and Escherichia coli (involved in agricultural animal infections), improving the results obtained with its individual or even physical mixed precursors [glufosinate and Cu(NO3)2]. It is also an effective pesticide against germination and plant growth of the weed Raphanus sativus, an invasive species in berries and vines crops, demonstrating that the construction of MOFs based on herbicide and antibacterial/antifungal units is a promising strategy to achieve multifunctional agrochemicals. To the best of our knowledge, this first report on the synthesis of an MOF based on agrochemicals (what we have named AgroMOF) opens new ways on the safe and efficient MOF application in agriculture.

Pushing the Limits on the Intestinal Crossing of Metal-Organic Frameworks: An Ex Vivo and In Vivo Detailed Study.

Biocompatible nanoscaled metal-organic frameworks (nanoMOFs) have been widely studied as drug delivery systems (DDSs), through different administration routes, with rare examples in the convenient and commonly used oral administration. So far, the main objective of nanoMOFs as oral DDSs was to increase the bioavailability of the cargo, without considering the MOF intestinal crossing with potential advantages (e.g., increasing drug availability, direct transport to systemic circulation). Thus, we propose to address the direct quantification and visualization of MOFs' intestinal bypass. For that purpose, we select the microporous Fe-based nanoMOF, MIL-127, exhibiting interesting properties as a nanocarrier (great biocompatibility, large porosity accessible to different drugs, green and multigram scale synthesis, outstanding stability along the gastrointestinal tract). Additionally, the outer surface of MIL-127 was engineered with the biopolymer chitosan (CS@MIL-127) to improve the nanoMOF intestinal permeation. The biocompatibility and intestinal crossing of nanoMOFs is confirmed using a simple and relevant in vivo model, Caenorhabditis elegans; these worms are able to ingest enormous amounts of nanoMOFs (up to 35 g per kg of body weight). Finally, an ex vivo intestinal model (rat) is used to further support the nanoMOFs' bypass across the intestinal barrier, demonstrating a fast crossing (only 2 h). To the best of our knowledge, this report on the intestinal crossing of intact nanoMOFs sheds light on the safe and efficient application of MOFs as oral DDSs.

Oligoethylene Glycol Side Chains Increase Charge Generation in Organic Semiconductor Nanoparticles for Enhanced Photocatalytic Hydrogen Evolution.

Organic semiconductor nanoparticles (NPs) composed of an electron donor/acceptor (D/A) semiconductor blend have recently emerged as an efficient class of hydrogen-evolution photocatalysts. It is demonstrated that using conjugated polymers functionalized with (oligo)ethylene glycol side chains in NP photocatalysts can greatly enhance their H2 -evolution efficiency compared to their nonglycolated analogues. The strategy is broadly applicable to a range of structurally diverse conjugated polymers. Transient spectroscopic studies show that glycolation facilitates charge generation even in the absence of a D/A heterojunction, and further suppresses both geminate and nongeminate charge recombination in D/A NPs. This results in a high yield of photogenerated charges with lifetimes long enough to efficiently drive ascorbic acid oxidation, which is correlated with greatly enhanced H2 -evolution rates in the glycolated NPs. Glycolation increases the relative permittivity of the semiconductors and facilitates water uptake. Together, these effects may increase the high-frequency relative permittivity inside the NPs sufficiently, to cause the observed suppression of exciton and charge recombination responsible for the high photocatalytic activities of the glycolated NPs.

Propylene and butylene glycol: new alternatives to ethylene glycol in conjugated polymers for bioelectronic applications.

To date, many of the high-performance conjugated polymers employed as OECT channel materials make use of ethylene glycol (EG) chains to confer the materials with mixed ionic-electronic conduction properties, with limited emphasis placed on alternative hydrophilic moieties. While a degree of hydrophilicity is required to facilitate some ionic conduction in hydrated channels, an excess results in excessive swelling, with potentially detrimental effects on charge transport. This is therefore a subtle balance that must be optimised to maximise electrical performance. Herein a series of polymers based on a bithiophene-thienothiophene conjugated backbone was synthesised and the conventional EG chains substituted by their propylene and butylene counterparts. Specifically, the use of propylene and butylene chains was found to afford polymers with a more hydrophobic character, thereby reducing excessive water uptake during OECT operation and in turn significantly boosting the polymers' electronic charge carrier mobility. Despite the polymers' lower water uptake, the newly developed oligoether chains retained sufficiently high degrees of hydrophilicity to enable bulk volumetric doping, ultimately resulting in the development of polymers with superior OECT performance.

Polaron Delocalization in Donor-Acceptor Polymers and its Impact on Organic Electrochemical Transistor Performance.

Donor-acceptor (D-A) polymers are promising materials for organic electrochemical transistors (OECTs), as they minimize detrimental faradaic side-reactions during OECT operation, yet their steady-state OECT performance still lags far behind their all-donor counterparts. We report three D-A polymers based on the diketopyrrolopyrrole unit that afford OECT performances similar to those of all-donor polymers, hence representing a significant improvement to the previously developed D-A copolymers. In addition to improved OECT performance, DFT simulations of the polymers and their respective hole polarons also reveal a positive correlation between hole polaron delocalization and steady-state OECT performance, providing new insights into the design of OECT materials. Importantly, we demonstrate how polaron delocalization can be tuned directly at the molecular level by selection of the building blocks comprising the polymers' conjugated backbone, thus paving the way for the development of even higher performing OECT polymers.

A Robust and Biocompatible Bismuth Ellagate MOF Synthesized Under Green Ambient Conditions.

The first bioinspired microporous metal-organic framework (MOF) synthesized using ellagic acid, a common natural antioxidant and polyphenol building unit, is presented. Bi2O(H2O)2(C14H2O8)·nH2O (SU-101) was inspired by bismuth phenolate metallodrugs, and could be synthesized entirely from nonhazardous or edible reagents under ambient aqueous conditions, enabling simple scale-up. Reagent-grade and affordable dietary supplement-grade ellagic acid was sourced from tree bark and pomegranate hulls, respectively. Biocompatibility and colloidal stability were confirmed by in vitro assays. The material exhibits remarkable chemical stability for a bioinspired MOF (pH = 2-14, hydrothermal conditions, heated organic solvents, biological media, SO2 and H2S), attributed to the strongly chelating phenolates. A total H2S uptake of 15.95 mmol g-1 was recorded, representing one of the highest H2S capacities for a MOF, where polysulfides are formed inside the pores of the material. Phenolic phytochemicals remain largely unexplored as linkers for MOF synthesis, opening new avenues to design stable, eco-friendly, scalable, and low-cost MOFs for diverse applications, including drug delivery.

Side Chain Redistribution as a Strategy to Boost Organic Electrochemical Transistor Performance and Stability.

A series of glycolated polythiophenes for use in organic electrochemical transistors (OECTs) is designed and synthesized, differing in the distribution of their ethylene glycol chains that are tethered to the conjugated backbone. While side chain redistribution does not have a significant impact on the optoelectronic properties of the polymers, this molecular engineering strategy strongly impacts the water uptake achieved in the polymers. By careful optimization of the water uptake in the polymer films, OECTs with unprecedented steady-state performances in terms of [µC* ] and current retentions up to 98% over 700 electrochemical switching cycles are developed.

Water stable molecular n-doping produces organic electrochemical transistors with high transconductance and record stability.

From established to emergent technologies, doping plays a crucial role in all semiconducting devices. Doping could, theoretically, be an excellent technique for improving repressively low transconductances in n-type organic electrochemical transistors - critical for advancing logic circuits for bioelectronic and neuromorphic technologies. However, the technical challenge is extreme: n-doped polymers are unstable in electrochemical transistor operating environments, air and water (electrolyte). Here, the first demonstration of doping in electron transporting organic electrochemical transistors is reported. The ammonium salt tetra-n-butylammonium fluoride is simply admixed with the conjugated polymer poly(N,N'-bis(7-glycol)-naphthalene-1,4,5,8-bis(dicarboximide)-co-2,2'-bithiophene-co-N,N'-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide), and found to act as a simultaneous molecular dopant and morphology-additive. The combined effects enhance the n-type transconductance with improved channel capacitance and mobility. Furthermore, operational and shelf-life stability measurements showcase the first example of water-stable n-doping in a polymer. Overall, the results set a precedent for doping/additives to impact organic electrochemical transistors as powerfully as they have in other semiconducting devices.

Biomembrane-based organic electronic devices for ligand-receptor binding studies.

We present a simple, rapid method for forming supported lipid bilayers on organic electronic devices composed of conducting polymer electrodes using a solvent-assisted lipid bilayer formation method. These supported bilayers present protein recognition elements that are mobile, critical for multivalent binding interactions. Because these polymers are transparent and conducting, we demonstrate, by optical and electrical detection, the specific interactions of proteins with these biomembrane-based bioelectronic devices. This work paves the way for easy formation of biomembrane mimetics for sensing and detection of binding events in a label-free manner on organic electronic devices of more sophisticated architectures. Graphical abstract.

Facile Generation of Biomimetic-Supported Lipid Bilayers on Conducting Polymer Surfaces for Membrane Biosensing.

Membrane biosensors that can rapidly sense pathogen interaction and disrupting agents are needed to identify and screen new drugs to combat antibiotic resistance. Bioelectronic devices have the capability to read out both ionic and electrical signals, but their compatibility with biological membranes is somewhat limited. Supported lipid bilayers (SLBs) have served as useful biomimetics for a myriad of research topics involving biological membranes. However, SLBs are traditionally made on inert, rigid, inorganic surfaces. Here, we demonstrate a versatile and facile method for generating SLBs on a conducting polymer device using a solvent-assisted lipid bilayer (SALB) technique. We use this bioelectronic device to form both mammalian and bacterial membrane mimetics to sense the membrane interactions with a bacterial toxin (α-hemolysin) and an antibiotic compound (polymyxin B), respectively. Our results show that we can form high quality bilayers of both types and sense these particular interactions with them, discriminating between pore formation, in the case of α-hemolysin, and disruption of the bilayer, in the case of polymyxin B. The SALB formation method is compatible with many membrane compositions that will not form via common vesicle fusion methods and works well in microfluidic devices. This, combined with the massive parallelization possible for the fabrication of electronic devices, can lead to miniaturized multiplexed devices for rapid data acquisition necessary to identify antibiotic targets that specifically disrupt bacterial, but not mammalian membranes, or identify bacterial toxins that strongly interact with mammalian membranes.

An organic electrochemical transistor integrated with a molecularly selective isoporous membrane for amyloid-ß detection.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with severe memory loss and impaired cognitive skills. A common pathological change found in AD-affected brains is the accumulation of a peptide named amyloid-ß (Aß) that can form plaques. Aß aggregates are visible to structural scanning tools; however, these bulky and expensive instruments are accessible to trained personnel in clinical settings only, thus hampering timely diagnosis of the disease, particularly in low-resource settings. In this work, we design an organic electrochemical transistor (OECT) for in vitro detection of Aß aggregates in human serum. The OECT channel is integrated with a nanostructured isoporous membrane which has a strong affinity for Aß aggregates. The detection mechanism relies on the membrane capturing Aß aggregates larger than the size of its pores and thus blocking the penetration of electrolyte ions into the channel underneath. Combining the high transconductance of the OECT with the precise porosity and selectivity of the membrane, the device detects the presence of Aß aggregates in human serum samples with excellent sensitivity. This is the first-time demonstration of a biofunctionalized, nanostructured, and isoporous membrane integrated with a high-performance transistor for biosensing. This robust, low-power, non-invasive, and miniaturized sensor aids in the development of point-of-care tools for early diagnosis of AD.

On the Role of Contact Resistance and Electrode Modification in Organic Electrochemical Transistors.

Contact resistance is renowned for its unfavorable impact on transistor performance. Despite its notoriety, the nature of contact resistance in organic electrochemical transistors (OECTs) remains unclear. Here, by investigating the role of contact resistance in n-type OECTs, the first demonstration of source/drain-electrode surface modification for achieving state-of-the-art n-type OECTs is reported. Specifically, thiol-based self-assembled monolayers (SAMs), 4-methylbenzenethiol (MBT) and pentafluorobenzenethiol (PFBT), are used to investigate contact resistance in n-type accumulation-mode OECTs made from the hydrophilic copolymer P-90, where the deliberate functionalization of the gold source/drain electrodes decreases and increases the energetic mismatch at the electrode/semiconductor interface, respectively. Although MBT treatment is found to increase the transconductance three-fold, contact resistance is not found to be the dominant factor governing OECT performance. Additional morphology and surface energy investigations show that increased performance comes from SAM-enhanced source/drain electrode surface energy, which improves wetting, semiconductor/metal interface quality, and semiconductor morphology at the electrode and channel. Overall, contact resistance in n-type OECTs is investigated, whilst identifying source/drain electrode treatment as a useful device engineering strategy for achieving state of the art n-type OECTs.

Self-Assembled Cationic ß-Cyclodextrin Nanostructures for siRNA Delivery.

Functionalized cyclodextrin molecules assemble into a wide variety of superstructures in solution, which are of interest for drug delivery and other nanomaterial and biomaterial applications. Here we use a combined simulation and experimental approach to probe the coassembly of siRNA and cationic cyclodextrin (c-CD) derivatives into a highly stable gene delivery nanostructure. The c-CD form supramolecular structures via interdigitation of their aliphatic tails, analogous to the formation of lipid bilayers and micelles. The native conformation of siRNA is preserved by the encapsulating c-CD superstructure in an extensive hydrogen-bonding network between the positively charged side arms of c-CD and the negatively charged siRNA backbone. The stability of the complexation is confirmed using isothermal titration calorimetry, and the experimental/simulation codesign methodology opens new avenues for creation of highly engineerable gene delivery vectors.