KinomeMETA: a web platform for kinome-wide polypharmacology profiling with meta-learning.

Kinase-targeted inhibitors hold promise for new therapeutic options, with multi-target inhibitors offering the potential for broader efficacy while minimizing polypharmacology risks. However, comprehensive experimental profiling of kinome-wide activity is expensive, and existing computational approaches often lack scalability or accuracy for understudied kinases. We introduce KinomeMETA, an artificial intelligence (AI)-powered web platform that significantly expands the predictive range with scalability for predicting the polypharmacological effects of small molecules across the kinome. By leveraging a novel meta-learning algorithm, KinomeMETA efficiently utilizes sparse activity data, enabling rapid generalization to new kinase tasks even with limited information. This significantly expands the repertoire of accurately predictable kinases to 661 wild-type and clinically-relevant mutant kinases, far exceeding existing methods. Additionally, KinomeMETA empowers users to customize models with their proprietary data for specific research needs. Case studies demonstrate its ability to discover new active compounds by quickly adapting to small dataset. Overall, KinomeMETA offers enhanced kinome virtual profiling capabilities and is positioned as a powerful tool for developing new kinase inhibitors and advancing kinase research. The KinomeMETA server is freely accessible without registration at https://kinomemeta.alphama.com.cn/.

Leveraging intracellular ALDH1A1 activity for selective cancer stem-like cell labeling and targeted treatment via in vivo click reaction.

Inhibition of overexpressed enzymes is among the most promising approaches for targeted cancer treatment. However, many cancer-expressed enzymes are "nonlethal," in that the inhibition of the enzymes' activity is insufficient to kill cancer cells. Conventional antibody-based therapeutics can mediate efficient treatment by targeting extracellular nonlethal targets but can hardly target intracellular enzymes. Herein, we report a cancer targeting and treatment strategy to utilize intracellular nonlethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound, AAMCHO [N-(3,4,6-triacetyl- N-azidoacetylmannosamine)-cis-2-ethyl-3-formylacrylamideglycoside], selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1. Notably, azide labeling is more efficient in identifying tumorigenic cell populations than endogenous markers such as CD44. A dibenzocyclooctyne (DBCO)-toxin conjugate, DBCO-MMAE (Monomethylauristatin E), could next target the labeled CSCs in vivo via bioorthogonal Click reaction to achieve excellent anticancer efficacy against a series of tumor models, including orthotopic xenograft, drug-resistant tumor, and lung metastasis with low toxicity. A 5/7 complete remission was observed after single-cycle treatment of an advanced triple-negative breast cancer xenograft (~500 mm3).

Cytokine conjugation to enhance T cell therapy.

Adoptive T cell transfer (ACT) therapies suffer from a number of limitations (e.g., poor control of solid tumors), and while combining ACT with cytokine therapy can enhance effectiveness, this also results in significant side effects. Here, we describe a nanotechnology approach to improve the efficacy of ACT therapies by metabolically labeling T cells with unnatural sugar nanoparticles, allowing direct conjugation of antitumor cytokines onto the T cell surface during the manufacturing process. This allows local, concentrated activity of otherwise toxic cytokines. This approach increases T cell infiltration into solid tumors, activates the host immune system toward a Type 1 response, encourages antigen spreading, and improves control of aggressive solid tumors and achieves complete blood cancer regression with otherwise noncurative doses of CAR-T cells. Overall, this method provides an effective and easily integrated approach to the current ACT manufacturing process to increase efficacy in various settings.

KinomeMETA: meta-learning enhanced kinome-wide polypharmacology profiling.

Kinase inhibitors are crucial in cancer treatment, but drug resistance and side effects hinder the development of effective drugs. To address these challenges, it is essential to analyze the polypharmacology of kinase inhibitor and identify compound with high selectivity profile. This study presents KinomeMETA, a framework for profiling the activity of small molecule kinase inhibitors across a panel of 661 kinases. By training a meta-learner based on a graph neural network and fine-tuning it to create kinase-specific learners, KinomeMETA outperforms benchmark multi-task models and other kinase profiling models. It provides higher accuracy for understudied kinases with limited known data and broader coverage of kinase types, including important mutant kinases. Case studies on the discovery of new scaffold inhibitors for membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase and selective inhibitors for fibroblast growth factor receptors demonstrate the role of KinomeMETA in virtual screening and kinome-wide activity profiling. Overall, KinomeMETA has the potential to accelerate kinase drug discovery by more effectively exploring the kinase polypharmacology landscape.

Computational chromatography: A machine learning strategy for demixing individual chemical components in complex mixtures.

Surface-enhanced Raman spectroscopy (SERS) holds exceptional promise as a streamlined chemical detection strategy for biological and environmental contaminants compared with current laboratory methods. Priority pollutants such as polycyclic aromatic hydrocarbons (PAHs), detectable in water and soil worldwide and known to induce multiple adverse health effects upon human exposure, are typically found in multicomponent mixtures. By combining the molecular fingerprinting capabilities of SERS with the signal separation and detection capabilities of machine learning (ML), we examine whether individual PAHs can be identified through an analysis of the SERS spectra of multicomponent PAH mixtures. We have developed an unsupervised ML method we call Characteristic Peak Extraction, a dimensionality reduction algorithm that extracts characteristic SERS peaks based on counts of detected peaks of the mixture. By analyzing the SERS spectra of two-component and four-component PAH mixtures where the concentration ratios of the various components vary, this algorithm is able to extract the spectra of each unknown component in the mixture of unknowns, which is then subsequently identified against a SERS spectral library of PAHs. Combining the molecular fingerprinting capabilities of SERS with the signal separation and detection capabilities of ML, this effort is a step toward the computational demixing of unknown chemical components occurring in complex multicomponent mixtures.

Nonlinear 3D Ligand-Based Metal-Organic Framework for Thermodynamic-Kinetic Synergistic Splitting of Mono-/Dibranched Hexane Isomers.

The selective splitting of hexane isomers without the use of energy-intensive phase-change processes is essential for the low-carbon production of clean fuels and also very challenging. Here, we demonstrate a strategy to achieve a complete splitting of the high-RON dibranched isomer from the monobranched and linear isomers, by using a nonlinear 3D ligand to form pillar-layered MOFs with delicate pore architecture and chemistry. Compared with its isoreticular MOFs with the same ted pillar but different linear 3D or linear 2D in-layer ligands, the new MOF constructed in this work, Cu(bhdc)(ted)0.5 (ZUL-C5), exhibited an interesting "channel switch" effect which creates pore space with reduced window size and channel dimensionality together with unevenly distributed alkyl-rich adsorption sites, contributing to a greatly enhanced ability to discriminate between mono- and dibranched isomers. Evidenced by a series of studies including adsorption equilibrium/kinetics/breakthrough tests, guest-loaded single-crystal/powder XRD measurement, and DFT-D modeling, a thermodynamic-kinetic synergistic mechanism in the separation was proposed, resulting in a record production time for high-purity 2,2-dimethylbutane along with a high yield.

The combined exposure of polystyrene microplastics and high-fat feeding affects the intestinal pathology damage and microbiome in zebrafish.

The pervasive utilization of plastics and their integration into ecosystems has resulted in significant environmental issues, particularly the pollution of microplastics (MPs). In aquaculture, high-fat feed (HFD) is frequently employed to enhance the energy intake and economic fish production. This study utilized zebrafish as a model organism to investigate the impact of concurrent exposure to HFD and MPs on fish intestinal pathology damage and intestinal microbiome. The experimental design involved the division of zebrafish into two groups: one receiving a normal diet (ND) and the other receiving HFD. The zebrafish were exposed to a control group, as well as polystyrene (PS) MPs of varying sizes (5 and 50 µm). Histopathological examination revealed that the combination of 5 µm MPs and HFD resulted in the most significant damage to the zebrafish intestinal tract. Furthermore, gut microbiome assays indicated that exposure to MPs and HFD altered the composition of the gut microbiome. This study demonstrates that in aquaculture, the issue of HFD must be considered alongside concerns about MPs contamination, as both factors appear to have a combined effect on the intestinal pathology damage and intestinal microbiome. The findings of this research offer valuable insights for the improvement of fish farming practices.

Vertex Strategy in Layered 2D MOFs: Simultaneous Improvement of Thermodynamics and Kinetics for Record C2H2/CO2 Separation Performance.

Developing adsorbents with multiple merits in capacity, selectivity, mass transfer, and stability toward C2H2/CO2 separation is crucial and challenging for producing high-purity C2H2 for advanced polymers and the electronic industry. Here, we demonstrate a vertex strategy to create adsorbents combining these merits through rationally designing the vertex groups of a wavy-shaped framework in layered 2D metal-organic frameworks (MOFs) to finely regulate the local conformation and stacking interactions, which creates the optimal inter- and intralayer space to realize simultaneous improvement of adsorption thermodynamics and kinetics. Two new hydrolytically stable MOFs, ZUL-330 and ZUL-430, were prepared, and diverse experiments and modeling on both adsorption equilibrium and diffusion were performed. Record separation selectivities coupled with extraordinary dynamic C2H2 capacities were achieved for C2H2/CO2 mixtures with different proportions (50/50 or 10/5, v/v), along with a small diffusion barrier and fast mass transfer. Consequently, polymer-grade (99.9%) and electronic-grade (99.99%) C2H2 were obtained with excellent productivities of up to ∼6 mmol cm-3.

Genome-wide CRISPR screening reveals ADCK3 as a key regulator in sensitizing endometrial carcinoma cells to MPA therapy.

BACKGROUND: The effectiveness of conservative treatment of endometrial carcinoma (EC) with oral progesterone therapy, such as medroxyprogesterone acetate (MPA), can be blunted due to primary or acquired resistance, but the underlying mechanisms remain incompletely defined. METHODS: Genome-wide CRISPR screening was performed to identify potential regulators in response to MPA in Ishikawa cells. Crystal violet staining, RT-qPCR, western blotting, ChIP-qPCR and luciferase assays were employed to elucidate the p53-AarF domain-containing kinase 3 (ADCK3) regulatory axis and its roles in sensitizing EC cells to MPA treatment. RESULTS: ADCK3 is identified as a previously unrecognized regulator in response to MPA in EC cells. Loss of ADCK3 in EC cells markedly alleviated MPA-induced cell death. Mechanistically, loss of ADCK3 primarily suppresses MPA-mediated ferroptosis by abrogating arachidonate 15-lipoxygenase (ALOX15) transcriptional activation. Moreover, we validated ADCK3 as a direct downstream target of the tumor suppressor p53 in EC cells. By stimulating the p53-ADCK3 axis, the small-molecule compound Nutlin3A synergized with MPA to efficiently inhibit EC cell growth. CONCLUSIONS: Our findings reveal ADCK3 as a key regulator of EC cells in response to MPA and shed light on a potential strategy for conservative EC treatment by activating the p53-ADCK3 axis to sensitize MPA-mediated cell death.

Combined effects of high-fat diet and polystyrene microplastic exposure on microplastic bioaccumulation and lipid metabolism in zebrafish.

Extensive use of microplastics (MPs) threatens the safety of aquatic environments and hydrobionts. Increasing the weight of economic fish through high-fat diet (HFD) to increase production is common in aquaculture. However, little is known about the combined effects of MPs and HFD in fish. The aim of this study was to investigate the relationship between adiposity and MP bioaccumulation in fish. Using zebrafish as a vertebrate model, the content of polystyrene (PS) MPs in zebrafish tissues exposed to 5 and 50 µm of 1000 µg/L PS MPs was detected via confocal Raman spectroscopy in normal diet (ND) and HFD. The content of PS MPs in HFD group was significantly higher than that in ND group. The levels of hepatic lipids were significantly elevated in zebrafish subjected to HFD treatment, and this effect was aggravated by exposure to 5 µm PS MPs, and even caused liver injury. Transcriptomic analysis revealed that exposure to PS MPs interferes with hepatic lipid metabolism and energy homeostasis in zebrafish. These results suggests that in addition to controlling the use and performing proper recycling of plastic products in our daily life, we should not blindly increase the weight of fish through HFD. This aids protect the quality of economic fish and prevent MPs from being consumed by humans through the food chain. This study explored the interaction between fish feed culture and environmental pollutants to provide important reference for fish culture.

Characterization of a novel mycotombus-like virus from the plant-pathogenic fungus Phoma matteucciicola.

Here, we report a novel mycotombus-like mycovirus, tentatively named "Phoma matteucciicola RNA virus 2" (PmRV2), derived from the phytopathogenic fungus Phoma matteucciicola strain HNQH1. The complete PmRV2 genome is comprised of a positive-sense single-stranded RNA (+ssRNA) of 3,460 nucleotides (nt) with a GC content of 56.71%. Sequence analysis of PmRV2 indicated the presence of two noncontiguous open reading frames (ORFs) encoding a hypothetical protein and an RNA-dependent RNA polymerase (RdRp), respectively. PmRV2 contains a metal-binding 'GDN' triplet in motif C of RdRp, while most +ssRNA mycoviruses contained a 'GDD' motif in the same region. A BLASTp search showed that the RdRp amino acid sequence of PmRV2 was most closely related to the RdRp of Macrophomina phaseolina umbra-like virus 1 (50.72% identity) and Erysiphe necator umbra-like virus 2 (EnUlV2, 44.84% identity). Phylogenetic analysis indicated that PmRV2 grouped together with EnUlV2 within the recently proposed family "Mycotombusviridae".

A novel narnavirus isolated from Colletotrichum curcumae strain 780-2T.

The complete genome of a novel mycovirus, Colletotrichum curcumae narnavirus 1 (CcNV1), derived from the phytopathogenic fungus Colletotrichum curcumae strain 780-2T, was sequenced and analyzed. The full sequence of CcNV1 is 3,374 nucleotides in length and contains a single large open reading frame (ORF) encoding an RNA-dependent RNA polymerase (RdRp) of 1,087 amino acids with a molecular mass of 124.2 kDa that shares the closest similarity with that of Monilinia narnavirus H (53.02% identity). RdRp phylogeny analysis showed that CcNV1 is a new member of the proposed genus "Betanarnavirus" within the family Narnaviridae. This is the first report of a novel narnavirus infecting the phytopathogenic fungus C. curcumae, the causal agent of leaf blight of Curcuma wenyujin.

Protective role of circRNA CCND1 in ulcerative colitis via miR-142-5p/NCOA3 axis.

BACKGROUND: Increasing research indicates that circular RNAs (circRNAs) play critical roles in the development of ulcerative colitis (UC). This study aimed to determine the role of circRNA CCND1 in UC bio-progression, which has been shown to be downregulated in UC tissues. METHODS: Reverse transcription quantitative polymerase chain reaction was used to determine the levels of circRNA CCND1, miR-142-5p, and nuclear receptor coactivator-3 (NCOA3) in UC tissues and in lipopolysaccharide (LPS)-induced Caco-2 cells. Target sites of circRNA CCND1 and miR-142-5p were predicted using StarBase, and TargetScan to forecast potential linkage points of NCOA3 and miR-142-5p, which were confirmed by a double luciferase reporter-gene assay. Cell Counting Kit 8 and flow cytometry assays were performed to assess Caco-2 cell viability and apoptosis. TNF-α, IL-1ß, IL-6, and IL-8 were detected using Enzyme-Linked Immunosorbent Assay kits. RESULTS: CircRNA CCND1 was downregulated in UC clinical samples and LPS-induced Caco-2 cells. In addition, circRNA CCND1 overexpression suppressed LPS-induced apoptosis and inflammatory responses in Caco-2 cells. Dual-luciferase reporter-gene assays showed that miR-142-5p could be linked to circRNA CCND1. Moreover, miR-142-5p was found to be highly expressed in UC, and its silencing inhibited LPS-stimulated Caco-2 cell apoptosis and inflammatory responses. Importantly, NCOA3 was found downstream of miR-142-5p. Overexpression of miR-142-5p reversed the inhibitory effect of circRNA CCND1-plasmid on LPS-stimulated Caco-2 cells, and the effects of miR-142-5p inhibitor were reversed by si-NCOA3. CONCLUSION: CircRNA CCND1 is involved in UC development by dampening miR-142-5p function, and may represent a novel approach for treating UC patients.

Discovery and identification of a novel small molecule BCL-2 inhibitor that binds to the BH4 domain.

The B-cell lymphoma 2 (BCL-2) protein family plays a pivotal role in regulating the apoptosis process. BCL-2, as an antiapoptotic protein in this family, mediates apoptosis resistance and is an ideal target for cell death strategies in cancer therapy. Traditional treatment modalities target BCL-2 by occupying the hydrophobic pocket formed by BCL-2 homology (BH) domains 1-3, while in recent years, the BH4 domain of BCL-2 has also been considered an attractive novel target. Herein, we describe the discovery and identification of DC-B01, a novel BCL-2 inhibitor targeting the BH4 domain, through virtual screening combined with biophysical and biochemical methods. Our results from surface plasmon resonance and cellular thermal shift assay confirmed that the BH4 domain is responsible for the interaction between BCL-2 and DC-B01. As evidenced by further cell-based experiments, DC-B01 induced cell killing in a BCL-2-dependent manner and triggered apoptosis via the mitochondria-mediated pathway. DC-B01 disrupted the BCL-2/c-Myc interaction and consequently suppressed the transcriptional activity of c-Myc. Moreover, DC-B01 inhibited tumor growth in vivo in a BCL­2­dependent manner. Collectively, these results indicate that DC-B01 is a promising BCL-2 BH4 domain inhibitor with the potential for further development.

Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease.

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PPiase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies.

Molecular regulation of fungal secondary metabolism.

Many bioactive secondary metabolites synthesized by fungi have important applications in many fields, such as agriculture, food, medical and others. The biosynthesis of secondary metabolites is a complex process involving a variety of enzymes and transcription factors, which are regulated at different levels. In this review, we describe our current understanding on molecular regulation of fungal secondary metabolite biosynthesis, such as environmental signal regulation, transcriptional regulation and epigenetic regulation. The effects of transcription factors on the secondary metabolites produced by fungi were mainly introduced. It was also discussed that new secondary metabolites could be found in fungi and the production of secondary metabolites could be improved. We also highlight the importance of understanding the molecular regulation mechanisms to activate silent secondary metabolites and uncover their physiological and ecological functions. By comprehensively understanding the regulatory mechanisms involved in secondary metabolite biosynthesis, we can develop strategies to improve the production of these compounds and maximize their potential benefits.

Regulatory T Cells Secrete IL10 to Suppress Neuroinflammation in Early Stage after Subarachnoid Hemorrhage.

Objective: Accumulating evidence supports neuroprotective effects of regulatory T cells (Tregs) in response to brain injury. However, the precise mechanisms underlying the beneficial effects of Tregs on suppressing neuroinflammation after subarachnoid hemorrhage (SAH) remain unclear. Methods: We performed flow cytometry to detect the infiltration of Tregs into the brain at different time points after SAH. Behavioral tests, including Adhesive and Rotarod, were performed to assess neurological deficits in mice after SAH. Bulk RNA sequencing was used to investigate the transcriptomic change of Tregs infiltrating into the brain after SAH. qPCR was performed to verify the variation of inflammatory cytokines expression in the brain after Tregs exogenous infusion. FoxP3-DTR mice and Il10 gene KO mice were used to explore the mechanism of Tregs inhibiting neuron apoptosis after infiltrating the brain following SAH onset. Results: Peripheral Tregs infiltrated into the brain one day after SAH and gradually accumulated in the hemorrhagic hemisphere. An exogenous infusion of Tregs significantly improved the neurological function of mice after SAH, while poor recovery of neurological function was observed in Tregs depletion mice. Transcriptome sequencing data suggested that the immunosuppressive function of brain-infiltrated Tregs was significantly upregulated. qPCR showed that the expression of pro-inflammatory cytokines decreased in the brain of SAH mice after exogenous Tregs infusion. Bioinformatic analysis revealed that IL-10 and other cytokines secreted by brain-infiltrated Tregs were upregulated after SAH. Moreover, exogenous infusion of Il10 gene KO Tregs did not totally improve neurological function in SAH mice. Conclusions: Tregs infiltrated into the brain in the early stage after SAH and exerted neuroprotective effect by secreting IL-10 to suppress neuroinflammation and reduce neuron apoptosis.

Modulating the Reaction Configuration by Breaking the Structural Symmetry of Active Sites for Efficient Photocatalytic Reduction of Low-concentration CO2.

Photocatalytic conversion of low-concentration CO2 is considered as a promising way to simultaneously mitigate the environmental and energy issues. However, the weak CO2 adsorption and tough CO2 activation process seriously compromise the CO production, due to the chemical inertness of CO2 molecule and the formed fragile metal-C/O bond. Herein, we designed and fabricated oxygen vacancy contained Co3 O4 hollow nanoparticles on ordered macroporous N-doped carbon framework (Vo-HCo3 O4 /OMNC) towards photoreduction of low-concentration CO2 . In situ spectra and ab initio molecular dynamics simulations reveal that the constructed oxygen vacancy is able to break the local structural symmetry of Co-O-Co sites. The formation of asymmetric active site switches the CO2 configuration from a single-site linear model to a multiple-sites bending one with a highly stable configuration, enhancing the binding and structural polarization of CO2 molecules. As a result, Vo-HCo3 O4 /OMNC shows unprecedent activity in the photocatalytic conversion of low-concentration CO2 (10 % CO2 /Ar) under laboratory light source or even natural sunlight, affording a syngas yield of 337.8 or 95.2 mmol g-1 h-1 , respectively, with an apparent quantum yield up to 4.2 %.

Tunable Confined Aliphatic Pore Environment in Robust Metal-Organic Frameworks for Efficient Separation of Gases with a Similar Structure.

The fine-tuning of the pore structure of metal-organic frameworks (MOFs) is of critical importance to developing energy-efficient processes for the challenging separation of structurally similar molecules. Herein, we demonstrate a strategy to realize a quasi-three-dimensional refinement of the pore structure that utilizes the tunability of ring size and number in polycycloalkane-dicarboxylate ligands. Two hydrolytically stable MOFs with a confined aliphatic pore environment, ZUL-C1 and ZUL-C2, were, for the first time, synthesized and applied in separating low-concentration C2-C3 hydrocarbons from natural gas and ultralow-concentration Xe from used nuclear fuel (UNF) off-gas. Validated by X-ray diffraction and modeling, an expansion of the polycycloalkane moiety enables sub-angstrom contraction in specific directions and forms a pore surface with more alkyl sites, which affords stronger trapping of guest molecules with relatively higher polarizability. The resultant material exhibits record C2H6/CH4 and C3H8/CH4 selectivities coupled with a benchmark low-pressure C2H6 capacity in alkane mixture separation and also a benchmark Xe capacity at extremely diluted feed concentration and record Kr productivity for the Xe/Kr (20:80, v/v) mixture in Xe/Kr separation.

Highly Efficient Separation of C8 Aromatic Isomers by Rationally Designed Nonaromatic Metal-Organic Frameworks.

The separation of C8 aromatics (xylenes and ethylbenzene) remains one of the most challenging industrial separations due to their similar structures and properties. Suitable adsorbents that can distinguish the small differences among isomers are urgently demanded. Herein, we demonstrate a strategy to realize the precise discrimination of C8 aromatics by constructing a nonaromatic confined pore environment with mixed polycycloalkane-type ligands. The nonaromatic low-polar pore environment avoids strong convergent interactions between the framework and the common phenyl rings while creating possibilities to amplify the difference between host-guest/guest-guest interactions regarding the different methyl (ethyl) group positions of isomers. The resultant metal-organic framework, ZUL-C3, with either tetragonal or monoclinic lattice, exhibits outstanding separation performance for C8 aromatics, not only realizing the simultaneous separation of four isomers from each other but also setting a benchmark for the dynamic separation performance of OX/PX and OX/MX.