Host-guest Interactions Research Articles

Exploring the Potential of Beta-Cyclodextrin-Based MIL-101(Cr) for Pharmaceutical Removal from Wastewater: A Combined Density Functional Theory and Molecular Simulations Study.

Pharmaceutical contaminants pose significant risks to ecosystems and human health, necessitating effective removal strategies. This research focuses on developing advanced adsorbents for removing pharmaceutical pollutants from the environment. Metal-organic frameworks (MOFs), specifically MIL-101(Cr) functionalized with biodegradable beta-cyclodextrin (β-CDex), were investigated as potential nanocomposite adsorbents for the removal of ketorolac (KTRK), naproxen (NPXN), and tramadol (TRML). The study employed molecular simulations and density functional theory (DFT) calculations to explore the interactions between the pollutants and adsorbents. Analyses of DFT results, including electrostatic potential, ionization energy, density of states, and molecular orbital analysis, provided insights into the reactivity of pollutants and adsorbents. Additionally, the structural properties of the adsorbents, such as fractional free volume, radius of gyration, and system energies, were thoroughly examined. Molecular dynamics (MD) and Monte Carlo (MC) simulations were used to evaluate the adsorption capacities of MIL-101(Cr) for the target pharmaceutical pollutants. The results demonstrated the superior adsorption performance of the nanocomposite adsorbent, particularly for KTRK, with an adsorption energy of -1934 kcal/mol, compared to the pristine MIL-101(Cr), which had an adsorption energy of -1916 kcal/mol. This enhanced adsorption is attributed to the optimal molecular fit, guest-host solid interactions, and the selective encapsulation capabilities of β-CDex. This research highlights the potential of MOF-based nanocomposites as effective and sustainable solutions for pharmaceutical pollution. By advancing the understanding of molecular interactions through simulations, this study contributes to developing innovative adsorbents for wastewater treatment and the protection of water resources.

A Double‐walled Noncovalent Carbon Nanotube by Columnar Packing of Nanotube Fragments

AbstractHerein, we report the synthesis of double‐walled noncovalent carbon nanotubes (CNTs) through host–guest complexation of nanotube fragments and tube‐forming crystal engineering. As the smallest fragment of double‐walled CNTs, a host–guest complex of perfluorocycloparaphenylene (PFCPP) and carbon nanobelt (CNB) was synthesized by mixing them in solvents. The immediate complexation of the PF[12]CPP⸧(6,6)CNB complex with a remarkably high association constant (Ka) of 2×105 L/mol was observed. Time‐dependent 1H NMR and thermogravimetry measurements revealed that the stability of (6,6)CNB was significantly improved by encapsulation. X‐ray crystallography confirmed the robust belt‐in‐ring structure of this complex. As indicated by the short distance between PF[12]CPP and (6,6)CNB (2.8 Å), intermolecular orbital interactions exist between the belt and the ring, which were further supported by theoretical calculation and phosphorescence quenching experiments. While the PF[12]CPP⸧(6,6)CNB complex adopts various crystal packing structures, chloroform was discovered to be a magic “glue” solvent inducing one‐dimensional alignment of the PF[12]CPP⸧(6,6)CNB complex to build an unprecedented double‐walled noncovalent CNT structure.

End Group Effects on Anion Binding in Tetraglycine Peptide: A Computational Study.

The importance of anions in various processes has led to a search for molecules that can effectively recognize and interact with these anions. This study explores how the tetraglycine [(Gly)4] peptide in its zwitterionic, neutral, and terminally capped forms acts as a receptor for H2PO4 - and HSO4 - anions within the framework of supramolecular host-guest chemistry. Using molecular dynamics (MD) simulations, we obtained the conformations of the receptor-anion complexes. Density functional theory (DFT), quantifies the complexes' interaction energies in both gas and solvent phases. Proton transfer within the zwitterionic complex with H2PO4 - anion alters peptide charge distribution, affecting its conformation and binding site arrangement, as analysed by quantum mechanics/molecular mechanics (QM/MM) methods. Symmetry-adapted perturbation theory (SAPT) and noncovalent interactions analysis highlight the role of electrostatic interactions in these receptor-anion complexes. It emphasizes the key interactions such as N-H⋅⋅⋅⋅O and O-H⋅⋅⋅O=C between the peptide backbone and anions and elucidates the molecular recognition mechanism driven by crucial noncovalent interactions. The termination of the peptide's end groups modulates anion binding sites from the backbone to the charged N-terminal, resulting in distinct binding sites. Our findings provide insights for designing peptides tailored to function as anion receptors in diverse supramolecular chemistry applications.

Simultaneous Suppression of Multilayer Ion Migration via Molecular Complexation Strategy toward High-Performance Regular Perovskite Solar Cells.

The migration and diffusion of Li+, I- and Ag impedes the realization of long-term operationally stable perovskite solar cells (PSCs). Herein, we report a multifunctional and universal molecular complexation strategy to simultaneously stabilize hole transport layer (HTL), perovskite layer and Ag electrode by the suppression of Li+, I- and Ag migration via directly incorporating bis(2,4,6-trichlorophenyl) oxalate (TCPO) into HTL. Meanwhile, TCPO co-doping results in enhanced hole mobility of HTL, advantageous energy band alignment and mitigated interfacial defects, thereby leading to facilitated hole extraction and minimized nonradiative recombination losses. TCPO-doped regular device achieves a peak power conversion efficiency (PCE) of 25.68 % (certified 25.59 %). The unencapsulated TCPO doped devices maintain over 90 % of their initial efficiencies after 730 h of continuous operation under one sun illumination, 2800 h of storage at 30 % relative humidity, and 1200 h of exposure to 65 °C, which represents one of the best stabilities reported for regular PSCs. This work provides a new approach to enhance the PCE and long-term stability of PSCs by host-guest complexation strategy via rational design of multifunctional ligand molecules.

A Double-walled Noncovalent Carbon Nanotube by Columnar Packing of Nanotube Fragments.

Herein, we report the synthesis of double-walled noncovalent carbon nanotubes (CNTs) through host-guest complexation of nanotube fragments and tube-forming crystal engineering. As the smallest fragment of double-walled CNTs, a host-guest complex of perfluorocycloparaphenylene (PFCPP) and carbon nanobelt (CNB) was synthesized by mixing them in solvents. The immediate complexation of the PF[12]CPP⸧(6,6)CNB complex with a remarkably high association constant (Ka) of 2×105 L/mol was observed. Time-dependent 1H NMR and thermogravimetry measurements revealed that the stability of (6,6)CNB was significantly improved by encapsulation. X-ray crystallography confirmed the robust belt-in-ring structure of this complex. As indicated by the short distance between PF[12]CPP and (6,6)CNB (2.8 Å), intermolecular orbital interactions exist between the belt and the ring, which were further supported by theoretical calculation and phosphorescence quenching experiments. While the PF[12]CPP⸧(6,6)CNB complex adopts various crystal packing structures, chloroform was discovered to be a magic "glue" solvent inducing one-dimensional alignment of the PF[12]CPP⸧(6,6)CNB complex to build an unprecedented double-walled noncovalent CNT structure.

Shrinkable Hydrogels through Host–Guest Interactions: A Robust Approach to Obtain Tubular Cell‐Laden Scaffolds with Small Diameters

AbstractThe availability of realistic in vitro models is crucial for tissue engineering, disease modeling, and drug screening assays. However, reproducing the complex shapes and intricate structures of naturally occurring tissues or organs in the presence of functional cells remains a challenge. For example, it is still not trivial to obtain cell‐laden tubular structures on a micrometer scale present in the nephrons of the human kidney. Here, a unique hydrogel‐based shrinking approach making use of host–guest interactions to decrease the diameters of the preformed hydrogel tubules seeded with cells is proposed as a tool to overcome the abovementioned challenge. The hydrogels are composed of covalently crosslinked methacrylated hyaluronic acid and methacrylated dextran modified with either cyclodextrin or adamantane groups that can form dynamic bonds. The hydrogels are initially formed in the presence of small‐molecule competitors that block any interpolymer host–guest interactions, and the shrinking process is triggered by the release of these competitor molecules. The high shrinking efficiency with a shrinking factor up to eight times in volume and robust cytocompatibility make the host‐guest‐based shrinking approach an appealing tool to obtain hydrogel tubular in vitro models with the desired dimensions on demand.

A Ni4O4-cubane-squarate coordination framework for molecular recognition.

Molecular recognition is a fundamental function of natural systems that ensures biological activity. This is achieved through the sieving effect, host-guest interactions, or both in biological environments. Recent advancements in multifunctional proteins reveal a new dimension of functional organization that goes beyond single-function molecular recognition, emphasizing the need for artificial multifunctional materials in industrial applications. Herein, we have designed a porous Ni4O4-cubane squarate coordination polymer as an artificial molecular recognition host, drawing inspiration from the structural and functional features of natural enzymes. A comprehensive assessment of the material's ability to distinguish target species under different operating conditions was carried out. The results confirm its sieving function through hexane isomers separation, host-guest interaction function via xenon/krypton separation, and dual presence of sieving and interaction through carbon dioxide/nitrogen separation. Additionally, the material demonstrates good stability and feasibility for large-scale production, indicating its practical potential. Our findings provide a bio-inspired multifunctional recognition material for chemical separations as proof-of-concept while offering solutions to advance artificial multifunctional materials adaptable to other applications beyond chemical separations.

Pore configuration control in hybrid azolate ultra-microporous frameworks for sieving propylene from propane.

Developing porous adsorbents for the complete sieving of propylene/propane mixtures represents an alternative method to energy-intensive cryogenic distillation processes. However, the similar physical properties of these molecules and the inherent trade-off among adsorption capacity, selectivity, diffusion kinetic and host-guest binding interactions in molecular sieving adsorbents makes their separation challenging. Here we report the separation of propylene/propane mixtures through a crystalline porous material (HAF-1) that features channels and shrinkage throats-the latter defined as narrower channels that connect the main channels and a molecular pocket-where the throat aperture is between the kinetic diameters of propylene and propane. Single-crystal X-ray diffraction and computational simulation reveal that the shrinkage channels and hanging molecular pockets are key to ensure high sieving efficiency and high propylene adsorption capacity. Dynamic breakthrough experiments show that HAF-1 enables the achievement of high-purity (≥99.7%) propylene with a productivity of 33.9 l kg-1 by just one adsorption-desorption circle from propylene/propane mixtures.

A Supramolecular Self-Assembled Nanoprodrug for Enhanced Ferroptosis Therapy.

Ferroptosis can induce cell death that leverages Fe2+-triggered Fenton reactions within living organisms, leading to an excessive accumulation of lipid peroxides (LPOs) and inducing cell death. Ferroptosis can effectively circumvent the inevitable drug resistance encountered with traditional apoptotic therapies. However, several issues remain in the clinical application of ferroptosis anticancer therapy, primarily due to the poor efficiency of intracellular Fenton reaction. To address this issue, we developed a supramolecular self-assembled codelivery nanoprodrug (DOX@C18Fc-Q[7] NPs) composed of ferrocene (Fc)-based supramolecular amphiphiles (C18Fc-Q[7]) and a nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) activator (doxorubicin, DOX). The C18Fc-Q[7] is based on Fc linked to a hydrophobic long-chain alkane via a disulfide linkage, which interacts with hydrophilic Q[7] to form self-assembled amphiphiles. Importantly, the host-guest interaction between Q[7] and Fc effectively enhances the solubility of Fc while maintaining the stability of the Fe2+ source. Moreover, C18Fc-Q[7] also acts as a good carrier for loading DOX due to its good self-assembly. In cancer cells, elevated glutathione (GSH) triggers the disassembly of nanoprodrug, leading to the release of DOX, which upregulates NOX4 expression and increases H2O2 level, thereby promoting an efficient Fenton reaction for Fc-induced ferroptosis. Moreover, DOX induces cell death through apoptosis, providing a synergistic effect to further enhance the ferroptosis therapy. In vivo studies have demonstrated that this enhanced ferroptosis therapy effectively inhibits tumor growth and metastasis while maintaining good biosafety.

Self-Healing, Electrically Conductive, Antibacterial, and Adhesive Eutectogel Containing Polymerizable Deep Eutectic Solvent for Human Motion Sensing and Wound Healing.

Flexible electronic devices such as wearable sensors are essential to advance human-machine interactions. Conductive eutectogels are promising for wearable sensors, despite their challenges in self-healing and adhesion properties. This study introduces a multifunctional eutectogel based on a novel polymerizable deep eutectic solvent (PDES) prepared by the incorporation of diallyldimethylammonium chloride (DADMAC) and glycerol in the presence of polycyclodextrin (PCD)/dopamine-grafted gelatin (Gel-DOP)/oxidized sodium alginate (OSA). The synthesized eutectogel has reversible Schiff-base bonds, hydrogen bonds, and host-guest interactions, which enable rapid self-healing upon network disruption. GPDO-15 eutectogel has significant tissue adhesion, high stretchability (419%), good ionic conductivity (0.79 mS·cm-1), and favorable antibacterial and self-healing properties. These eutectogels achieve 90% antibacterial effect, show excellent biocompatibility, and can be used as sensors to monitor human activities with strong stability and durability. The in vivo studies indicate that the eutectogels can improve the wound healing process which makes them an effective option for biological dressings.

Solvent-Controlled Separation of Integratively Self-Sorted Pd2LA 2LB 2 Coordination Cages.

The integrative implementation of multiple different components into metallosupramolecular self-assemblies requires sophisticated strategies to avoid the formation of statistical mixtures. Previously, the key focus was set on thermodynamically driven reactions of simple homoleptic into complex heteroleptic structures. Using Pd2LA 2LB 2-type coordination cages, we herein show that integrative self-sorting can be reversed by a change of solvent (from DMSO to MeCN) to favor narcissistic re-segregation into coexisting homoleptic species Pd2LA 4 and Pd3LB 6. Full separation ("unsorting") back to a mixture of the homoleptic precursors was finally achieved by selective precipitation of Pd3LB 6 with anionic guest G1 from MeCN, keeping pure Pd2LA 4 in solution. When a mixture of homoleptic Pd3LB 6 and heteroleptic Pd2LA 2LB 2 is exposed to a combination of two different di-anions (G1 and G2) in DMSO, selective guest uptake gives rise to two defined coexisting host-guest complexes. A joint experimental and deep theoretical investigation via liquid-state integral equation theory of the reaction thermodynamics on a molecular level accompanied by solvent distribution analysis hints at solvent expulsion from Pd2LA 4 to favor the formation of Pd2LA 2LB 2 in DMSO as the key entropic factor for determining the solvent-specific modulation of the cage conversion equilibrium.

Host-Guest Assemblies of Polyoxovanadate Clusters as Supramolecular Catalysts.

Supramolecular functional materials can be used to overcome some of the most challenging tasks in materials science, where the dynamic nature of supramolecular interactions can be leveraged to fine-tune the properties of the material. The Lindqvist hexavanadate family of polyoxometalates are interesting candidates for supramolecular materials due to their redox and Lewis acid properties that enable their application inenergy conversion or catalysis. Despite their promising potential, hexavanadate clusters are underrepresented in supramolecular materials, mainly due to the synthetic challenges related to their inherent reactivity. In this work, pillar[5]arene was successfully grafted onto a Lindqvist hexavanadate and the resulting structure was confirmed by single crystal X-ray diffraction, presenting the first example of a crystal structure of a polyoxometalate covalently functionalized with a pillar[5]arene. By introducing a ditopic guest molecule that could interlink pillar[5]arene moieties, host-guest interactions were leveraged as the driving force for the formation of supramolecular assemblies incorporating hexavanadate clusters in a controlled manner. The enhanced catalytic performance of the resulting aggregates confirmed their potential application as functional catalytic materials. This novel approach for developing hexavanadate-based catalysts reported here showcases the potential of using host-guest interactions as a means to introduce catalytically active metal-oxo clusters into supramolecular frameworks.

Interfacial Charge Transfer in One-Dimensional AgBr Encapsulated inside Single-Walled Carbon Nanotube Heterostructures.

The advent of one-dimensional van der Waals heterostructure (1D vdWH) nanomaterials has provided valuable opportunities for the advancement of electronic or optical devices, as well as for exploring various condensed matter phenomena. Electron transfer is a fundamental process in host-guest interactions, significantly influencing nanoscale physicochemical processes. Elucidating the mechanism by which the host influences the electronic structure of the guest is essential for elucidating these interactions. This study reports the successful synthesis of a material system consisting of precisely resolved AgBr nanowires encapsulated within single-walled carbon nanotubes (SWCNTs) that has been successfully synthesized and utilized to investigate the intrinsic electron transfer across 1D vdWHs. Cyclic voltammetry (CV) was employed to investigate the 1D vdWH interaction between AgBr and SWCNTs, which provided a more intuitive and accurate characterization of the charge transfer from SWCNTs to AgBr. Furthermore, Kelvin probe force microscopy showed a 149 mV reduction in the average surface potential of carbon nanotubes after AgBr filling, supporting the efficacy of CV in probing electron dynamics in 1D vdWHs. Finally, theoretical calculations indicated a charge transfer of 0.11 e- per simulation cell, reinforcing the effectiveness of CV in assessing the interactions within 1D vdWHs.

Single Molecular Dispersion of Crown Ether-Decorated Cobalt Phthalocyanine on Carbon Nanotubes for Robust CO2 Reduction through Host-Guest Interactions.

Immobilizing molecular catalysts on electro-conductive supports (for example, multi-walled carbon nanotubes, CNTs) represent a promising way to well-defined catalyst/support interfaces, which has shown appreciable performance for catalytic transformation. However, their full potential is far from achieved due to insufficient utilization of the intrinsic activity for each immobilized molecular catalyst, especially at loadings that should allow decent current densities. In the present work, we discover host-guest interaction between tetra-crown ether substituted cobalt phthalocyanine and metal ions, for example K+ ions, not only eliminate catalyst aggregation at immobilization procedures but also reinforce catalyst/support interactions by additional electrostatic attractions under operational conditions. Through simple dip-coating procedures, a successful single molecular dispersion is achieved. Such a catalyst/electrode interface is stable and can selectively catalyze CO2-to-CO conversion with Faradaic efficiency over 96%. Importantly, this interface maintains an almost unchanged turnover frequency (TOF) across all loading conditions, implying a full utilization of the intrinsic activity of supported molecular catalysts. Therefore, a simultaneous achievement of high TOF and high current density (TOF of 111 s-1 at 38 mA cm-2) is achieved, in an aqueous H-type electrolyzer at an overpotential of 570 mV.

Encapsulation of an Au25 Nanocluster inside a Porphyrin Nanoring Enhances Singlet Oxygen Generation and Photo-Electrocatalytic CO2 Reduction.

The synthesis of molecular host-guest complexes with enhanced performance, relative to those of their components, is a central theme in supramolecular chemistry. Here we explore a host-guest system consisting of an atomically precise gold nanocluster bound inside a zinc porphyrin nanoring. UV/Vis absorption and fluorescence titrations with different sized nanorings revealed strong binding between a pyridinethiol-coated Au25 nanocluster and a nanoring consisting of six zinc porphyrin units, and complexation is confirmed by mass spectrometry. Formation of this assembly enhances the stability of the gold nanocluster. The host-guest complex also exhibits remarkable activity and selectivity for photochemical CO2 to CO conversion and singlet oxygen generation.

Single Molecular Dispersion of Crown Ether‐Decorated Cobalt Phthalocyanine on Carbon Nanotubes for Robust CO2 Reduction through Host‐Guest Interactions

AbstractImmobilizing molecular catalysts on electro‐conductive supports (for example, multi‐walled carbon nanotubes, CNTs) represent a promising way to well‐defined catalyst/support interfaces, which has shown appreciable performance for catalytic transformation. However, their full potential is far from achieved due to insufficient utilization of the intrinsic activity for each immobilized molecular catalyst, especially at loadings that should allow decent current densities. In the present work, we discover host–guest interaction between tetra‐crown ether substituted cobalt phthalocyanine and metal ions, for example K+ ions, not only eliminate catalyst aggregation at immobilization procedures but also reinforce catalyst/support interactions by additional electrostatic attractions under operational conditions. Through simple dip‐coating procedures, a successful single molecular dispersion is achieved. Such a catalyst/electrode interface is stable and can selectively catalyze CO2‐to‐CO conversion with Faradaic efficiency over 96%. Importantly, this interface maintains an almost unchanged turnover frequency (TOF) across all loading conditions, implying a full utilization of the intrinsic activity of supported molecular catalysts. Therefore, a simultaneous achievement of high TOF and high current density (TOF of 111 s−1 at 38 mA cm−2) is achieved, in an aqueous H‐type electrolyzer at an overpotential of 570 mV.

Encapsulation of an Au25 Nanocluster inside a Porphyrin Nanoring Enhances Singlet Oxygen Generation and Photo‐Electrocatalytic CO2 Reduction

AbstractThe synthesis of molecular host–guest complexes with enhanced performance, relative to those of their components, is a central theme in supramolecular chemistry. Here we explore a host‐guest system consisting of an atomically precise gold nanocluster bound inside a zinc porphyrin nanoring. UV/Vis absorption and fluorescence titrations with different sized nanorings revealed strong binding between a pyridinethiol‐coated Au25 nanocluster and a nanoring consisting of six zinc porphyrin units, and complexation is confirmed by mass spectrometry. Formation of this assembly enhances the stability of the gold nanocluster. The host‐guest complex also exhibits remarkable activity and selectivity for photochemical CO2 to CO conversion and singlet oxygen generation.

Proximity Effects and Aggregation of Hamilton-Receptor Barbiturate Host-Guest Complexes Probed by Cross-Metathesis and ESI MS Analysis.

The molecular environment around supramolecular bonding systems significantly affects their stability and the assembly of host-guest complexes, most prominent for hydrogen bonds (H-bonds). Hamilton receptor-barbiturate host-guest complexes are well-known in solution, typically forming a 1:1 molar ratio complex. However, within a polymer matrix, these complexes can form higher-order assemblies, deviating from the standard 1:1 complex, which are challenging to characterize and often require lab-intensive methods. In this study, a novel Hamilton receptor (H) was equipped with cyclopentene moieties and used as a host to form host-guest complexes (H-B) with allobarbital (B), followed by covalent crosslinking. UV-Vis spectroscopy titration experiments in different solvents and at various temperatures revealed that polar solvents containing additional H-bonding sites significantly reduce the formation of the 1:1 H-B complex, as indicated by a reduced association constant. Higher-order aggregates (HH-dimer, HHH-trimer) were subsequently detected via an alkene cross-metathesis (CM) reaction to fix the assemblies covalently, followed by analysis via electrospray ionization mass spectrometry (ESI MS). This two-step method, firstly via CM fixation followed by ESI MS, was extended to study the H-B model complex within a polyisobutylene (PIB) matrix, presenting a direct method to analyze the complex host-guest assembly in solvent-free (polymer) environments.

Construction of Slide-Ring Polymers Based on Pillar[5]Arene/Alkyl Chain Host-Guest Interactions.

Slide-ring polymers exhibit distinctive mechanical properties, making them highly promising for applications in emerging fields such as energy storage devices and smart sensing. However, existing slide-ring polymer systems primarily rely on hydrophilic-hydrophobic interactions to achieve ring-axle interlocking in aqueous phases. This reliance limits the construction of slide-ring networks mainly to water-soluble polymers, excluding a diverse range of lipophilic polymers. Therefore, it is crucial to introduce efficient construction strategies that facilitate interpenetration in organic solvents, enabling the development of diverse slide-ring polymers and expanding their range and applications. Herein, by utilizing the pillar[5]arene/alkyl chain host-guest interactions, we successfully facilitated the interpenetration of a pillar[5]arene and poly(caprolactone), enabling the efficient construction of two slide-ring polymer networks in organic solvents. One of these two slide-ring polymers demonstrates a unique network deformation mechanism along with outstanding mechanical properties compared with the control covalently cross-linked polymer network, including maximum stress (4.43 vs 1.98 MPa), maximum strain (1285 vs 330 %), and toughness (35.4 vs 3.92 MJ/m3). More importantly, this strategy of making slide-ring polymers is highly versatile, given the wide range of macrocyclic arenes and alkyl chain-containing polymers it can accommodate.

Bimodal Array-Based Fluorescence Sensor and Microfluidic Technology for Protein Fingerprinting and Clinical Diagnosis.

Proteins play a crucial role in determining disease states in humans, making them prime targets for the development of diagnostic sensors. The developed sensor array is used to investigate global proteomic changes by fingerprinting multifactorial disease states in model urine simulating phenylketonuria and in serum from preeclamptic pregnant women. Here, we report a fluorescence-based chemical sensing array that exploits the host-guest interaction between cucurbit[7]uril (CB[7]) and fluorescent triphenylamine derivatives (TPA) to detect a range of proteins. Using linear discriminant analysis, we identify fluorescence fingerprints of 14 proteins with over 98% accuracy in buffer and human serum. The array is optimized on an automated droplet microfluidic-based platform, for high-throughput sensing with controlled composition and lower sample volumes. This sensor enables the discrimination of proteins in physiological buffer and human serum, with promising applications in disease diagnosis.