The interaction between metal-organic frameworks (MOFs) and nucleic acids offers significant potential for smart biosensing platforms. However, the underlying mechanisms remain elusive, limiting their practical implementation. Herein, we unveil the critical role of the electric double layer (EDL) at the MOF-solution interface in mediating nucleic acid adsorption, recognition, and desorption with a particular focus on mRNA detection. We demonstrate that primers immobilized on the surface of MOFs (MIL-101, Zn2Ph2Da, and UiO-66) hybridize with target mRNAs within the EDL slipping plane and that EDL compression significantly modulates hybridization efficiency. This EDL-governed recognition enables direct qPCR without total RNA extraction, facilitating point-of-care testing (POCT) detection. Using this approach, we achieved ultrasensitive detection of highly malignant and drug-resistant liver cancer biomarkers (ABCB1 mRNA) in serum, with detection limits down to 10-15 M. Furthermore, we developed a portable microfluidic device incorporating magnetic mRNA separation, providing a practical and integrated platform for clinical POCT applications.

The rapid growth of data volume and computing technologies has exposed the limitations of traditional encryption in terms of physical protection, system flexibility, and key management. Confronted with increasingly sophisticated attack threats, the static defense paradigm based on a single-mechanism encryption has become inadequate for maintaining information security. Therefore, integrating multimechanism strategies for collaborative defense within a dynamic architecture is essential to enhance information security. Here, we develop an algorithm-empowered encryption strategy using photocontrolled DNA origami nanostructures, which deeply integrates algorithms with molecular-scale programmable structural reconfiguration to establish a bioalgorithmic collaborative security framework. Rectangular DNA origami nanostructures serve as encoding physical substrates, storing digits and alphabets through binary mapping for information steganography. Additionally, dynamic connectors constructed from azobenzene-modified DNA strands establish linkages between DNA origami nanostructures, with the interstructural states precisely regulated via ultraviolet-visible (UV-vis) irradiation. Meanwhile, embedding the classical substitution-permutation ciphers into dynamically controllable nanostructures, combined with computationally driven key management, enables molecular-level information encryption and programmatic control. The cooperative encryption mechanism of substitution and permutation ciphers enhances information confusion and diffusion, while computational algorithms assist in optimizing the key layout and performing heuristic searches, further ensuring the security of molecular-level information processing. This work offers a promising perspective for research in information security and biointegrated intelligent systems.

Precise cancer diagnosis boosts survival rates, but liquid biopsy struggles to identify the tumor histotype from a single blood draw. We propose a Homologous Adhesion Identification (HAI) method that enables specific recognition between tumor extracellular vesicles (tEVs) and homologous tumor cell membrane-coated silica microsphere (TMS). The functionalized TMS exhibits an effective HAI property with high binding strength, speed, and biospecificity between tEVs and TMS, and their similar membrane structures facilitate efficient, rapid, and selective cancer diagnosis. The HAI method can effectively distinguish extracellular vesicles from normal and tumor sources and from different tumor histotypes and subtypes using just 10 μL of serum. It is versatile with replaceable cell membranes and lanthanide ions and supports diverse detection techniques like fluorescence, ultraviolet-visible spectrophotometry, electrochemistry, and electrochemiluminescence (ECL), with a minimum detection limit of 10 tEVs/mL. It accurately differentiates healthy and tumor blood samples in five animal models and shows significant potential for rapid cancer classification and therapeutic monitoring in clinical serum testing, both pre- and postoperatively.

MicroRNAs (miRNAs) are key regulators of disease-associated signaling pathways and serve as critical biomarkers for cancer. However, their accurate and reliable quantification in complex biofluids such as serum remains challenging because of their ultralow abundance and matrix interference, which severely limit their clinical and point-of-care testing (POCT) utility. To overcome this hurdle, we developed an electrochemical biosensor that integrates a UiO-66-NH2 enrichment strategy for the specific and rapid detection of miRNAs and validated it in clinical serum samples. UiO-66-NH2 was used to adsorb Texas Red-labeled miRNA aptamers, generating a high-density capture material (Apt-UiO-66-NH2) that selectively enriched target miRNAs. After enrichment, sodium tripolyphosphate (STPP) was employed to release aptamers─both those bound to miRNAs and those remaining unbound─from the MOF. The released single-stranded aptamers were then quantified with an electrochemical biosensor fabricated on a screen-printed electrode (SPE), allowing the determination of the target miRNA. The assay accomplishes rapid (<45 min) and sensitive detection of miR-21, miR-155, and miR-96 and can distinguish breast-cancer patients from postoperative recovery subjects. These results demonstrate the potential of this biosensor for real-time health monitoring and POCT miRNA analysis, particularly for breast-cancer diagnosis.

Homotypic targeting is the inherent ability of cells to preferentially interact with cells of the same type, a phenomenon seen in cell adhesion, tissue formation and immune responses. However, its potential remains underexploited. Here we report a strategy to substantially enhance homotypic targeting through extracellular vesicles secreted by cells. By engineering the surface of small extracellular vesicles (sEVs) with lanthanides, we amplify specific cell–sEV interactions by more than 25-fold, enabling the selective capture of sEVs by cells of the same lineage even in the presence of excess off-target sEVs. We term this effect ‘super homotypic targeting’. Super homotypic targeting provides a means to distinguish sEVs of different origins within highly heterogeneous sEV populations and enables two applications: using cells to detect specific sEVs and using sEVs to detect specific cells, specifically demonstrated here in the context of cancer detection from blood samples. Super homotypic targeting could hold potential for diagnostics, immunotherapy, drug delivery, rejuvenation and tissue engineering. Engineering the surface of small extracellular vesicles with lanthanide ions enhances homotypic targeting of cells through competitive coordination with sialic acid residues overexpressed on cancer cell surfaces, allowing the detection of cancer cell-derived small extracellular vesicles and circulating tumour cells.

Feline calicivirus (FCV) is a significant pathogen in cats, causing severe oral and respiratory diseases that threaten feline health. It is essential to find an efficient and rapid method for detecting FCV. Current detection methods, such as reverse transcription-quantitative polymerase chain reaction (RT-qPCR), are often labor-intensive and time-consuming. To overcome these limitations, this study developed a simplified mRNA detection method leveraging the multiadsorption properties of aptamers on metal-organic frameworks (MOFs). In this approach, RT-qPCR was performed on UiO-66 functionalized with reverse transcription (RT) primers that selectively hybridize to FCV RNA in biosamples. Nucleic acid amplification was initiated directly on the MOF surface, enabling quantitative analysis without prior RNA extraction. This method, termed surface-primed quantitative polymerase chain reaction (SP-qPCR), offers simple operation, ideal specificity, and high sensitivity with a limit of detection (LOD) of 1.91 copies/μL FCV in 90 min and excellent reproducibility (intra-assay and inter-assay coefficients of variation both less than 5%). Compared to commercial kits, SP-qPCR was faster and more cost-effective, eliminating the need for nucleic acid extraction. By integrating MOF-based sensing with qPCR, this strategy provides a rapid, efficient, and low-cost tool for FCV detection, with broad potential for clinical diagnostics.

Combination therapy to improve the immunotherapy response rate without causing treatment toxicity remains a significant challenge. Here, an artificial transmembrane oligopeptide, cholesterol-grafted polylysine (CPL), is synthesized to integrate mRNA with a monoclonal antibody into a single system. CPL with a 6% substitution degree is optimized and complexed with IFNβ mRNA to form CmRi nanoparticles. Subsequently, anti-PD-L1 monoclonal antibody (aPD-L1) is modified on the surface of CmRi to produce aCmRi nanoparticles. Notably, CPL facilitates cytosolic delivery via a membrane-interacting mechanism, thereby bypassing lysosomal degradation of mRNA. RNA sequencing analysis revealed that CPL promoted tumor cell apoptosis and upregulated MHC I expression by disrupting lysosomes in tumor cells. Additionally, CPL combined tumor cell-targeting and PD-L1 inhibitory functions of aPD-L1 with the multidimensional immunoadjuvant properties of in situ-expressed IFNβ. This approach overcame the side effects of IFNβ while fully leveraging its therapeutic potential. In a B16-F10 melanoma mouse model, aCmRi demonstrated a superior mRNA transfection rate (26.1%) and achieved the highest tumor suppression rate (89.9%) among all test formulations, without causing significant toxicity. This study presents a simple and versatile strategy to enhance the efficacy, selectivity, and safety of tumor immunotherapy in vivo.

Combination therapy, which involves the integration of two or more therapeutic agents to overcome off-target toxicity and drug resistance, is a cornerstone of cancer therapy because it targets different key pathways in a synergistic or additive manner. However, owing to the vast number of possible drug combinations, rational drug combinations based on molecular mechanisms associated with tumor therapy are challenging. Here, we propose a nitrogen-oxygen radical generator with mild photothermal properties that produces reactive oxygen/nitrogen oxide species through series-parallel reactions, and the reaction efficiency is improved under mild thermal conditions. These low-dosing free radicals destroy the antioxidant system of tumor-associated macrophages and lead to antitumor M1-type polarization, which act as the activated live-cell prodrug to induce in situ tumor cell death. Meanwhile, upregulation of PD-L1 expression on the surface of tumor cells occurs as a side effect. Fortunately, this side effect provides a solid foundation for the rationalization of nitrogen-oxygen radical generator-mediated macrophage polarization in combination with immune checkpoint inhibitor therapy such as an anti-PD-L1 monoclonal antibody. This strategy effectively reverses the immunosuppressive tumor microenvironment and shows a superior tumor suppression rate in a B16-F10 murine melanoma model, making the combination therapy more efficient, specific, and safe.

Inflammatory M1 macrophages play a crucial role in the pathogenesis of rheumatoid arthritis (RA). However, the simultaneous depletion and reprogramming of M1 macrophages in RA therapy remains a significant challenge. To address this issue, we developed a macrophage-targeting metal-amino acid framework (MAF) system with dual functions of methotrexate (MTX) delivery and reactive oxygen species (ROS) clearance. Specifically, Zn2 + ions and 9-fluorenylmethyloxycarbonyl-modified histidine (Fmoc-H) form a framework structure (pZFH) through coordination. The Fmoc-His-Thr-Lys-Pro-Arg peptide (Fmoc-HTKPR) can be easily doped into this structure at different ratios to modulate its targeting ability. MTX and Pt nanodots are loaded into the system by incorporating MTX during the pZFH preparation process and reducing platinum salts adsorbed on the surface of the pZFH-MTX nanoparticles (NPs). The targeting peptide enhanced the recognition and uptake of NPs by inflammatory macrophages. The release of MTX in response to the acidic inflammatory environment controls macrophage proliferation, while the Pt nanodots eliminated ROS, thereby promoting the polarization of proinflammatory M1 macrophages towards anti-inflammatory M2 macrophages. In an RA model, pZFH-MTX-Pt significantly reduced the expression of proinflammatory cytokines TNF-alpha and IL-6, alleviated joint swelling, and decreased bone hyperplasia. This system thus provides a synergistic RA treatment strategy that combines chemotherapy and immunotherapy.

Homotypic targeting is the inherent ability of cells for preferential interaction with cells of similar or identical types, a phenomenon commonly seen in cell adhesion, tissue formation, and immune responses. Unfortunately, its full potential remains largely untapped. Here we introduce an approach to drastically boost the homotypic targeting capabilities of cells via exosomes (nanoscale extracellular vesicles secreted by cells). By engineering exosome surfaces with lanthanides, we amplify specific cell-exosome interactions by more than 25-fold, significantly accelerating the selective capture of exosomes by cells of the same lineage. This substantial enhancement in cellular homophilicity opens up an entirely new class of applications, two of which we showcase here with unprecedented performance: using cells to detect specific exosomes and using exosomes to detect specific cells. The concept of “super homotypic targeting” offers enormous potential to transform cancer diagnostics, immunotherapy, targeted drug delivery, tissue engineering, and vaccine development. ### Competing Interest Statement H.-S.W., Y.L., T.D., S.S., and K.G. are inventors on a patent covering the exosome detection method. K.G. is an inventor on a patent covering the VIFFI imaging flow cytometer. N.N. and K.G. are shareholders of CYBO. M.S. and K.G. are shareholders of FlyWorks, Inc.

A highly sensitive and selective label-free impedimetric immunosensor based on AuNPs@pDA@NiCo2S4@MoS2 nanocomposite modified on the surface of a screen-printed electrode (SPE) was designed for the detection of interleukin-6 (IL-6). The distribution of NiCo2S4 nanoparticles on MoS2 nanosheets was able to prevent them from agglomerating. The polydopamine (pDA) layer was coated on the surface of NiCo2S4@MoS2 nanosheets by self-polymerization, which improved the stability and biocompatibility of the nanomaterial. The excellent reduction ability of pDA promoted the synthesis of gold nanoparticles (AuNPs), which increased the amount of antibody adsorption and the conductivity of the material. Finally, the antibody (Ab) of IL-6 was immobilized on the surface of AuNPs@pDA@NiCo2S4@MoS2 nanocomposite. Electrochemical impedance spectroscopy (EIS) was used to detect the change of impedance before and after the immune response between Ab and IL-6 antigen (IL-6). Under the optimal experimental conditions, the relative change in impedance and the logarithmic concentration of IL-6 showed a good linear relationship in the range 1.00 to 1.00 × 106 pg/mL, with a low detection limit of 0.97 pg/mL. In addition, the proposed immunosensor performed with good reproducibility, stability, and specificity. It was successfully applied to the determination of IL-6 in patient’s serum samples of head and neck carcinoma with recoveries of 98.40

The site-specific activation of bioorthogonal prodrugs has provided great opportunities for reducing the severe side effects of chemotherapy. However, the precise control of activation location, sustained drug production at the target site, and high bioorthogonal reaction efficiency in vivo remain great challenges. Here, we propose the construction of tumor cell membrane reactors in vivo to solve the above problems. Specifically, tumor-targeted liposomes with efficient membrane fusion capabilities are generated to install the bioorthogonal trigger, the amphiphilic tetrazine derivative, on the surface of tumor cells. These predecorated tumor cells act as many living reactors, transforming the tumor into a "drug factory" that in situ activates an externally delivered bioorthogonal prodrug, for example intratumorally injected transcyclooctene-caged doxorubicin. In contrast to the rapid elimination of cargo that is encapsulated and delivered by liposomes, these reactors permit stable retention of bioorthogonal triggers in tumor for 96 h after a single dose of liposomes via intravenous injection, allowing sustained generation of doxorubicin. Interestingly, an additional supplement of liposomes will compensate for the trigger consumed by the reaction and significantly improve the efficiency of the local reaction. This strategy provides a solution to the efficacy versus safety dilemma of tumor chemotherapy.

Coagulation factor XIa (FXIa) is associated with a low risk of bleeding and has been identified as an effective and safe target for the development of novel anticoagulant drugs. In this study, we established an ultrasensitive competitive dual-enzyme cascade signal amplification method for the quantitative analysis and screening of FXIa inhibitors. Due to the specific recognition of FXIa's active site by the aptamer AptE40, the AptE40-QDs-EK recognition probe modified with enterokinase (EK) and the aptamer AptE40, was attached to the MNPs-FXIa capture probe. When FXIa inhibitor was present, it competed with AptE40 for binding to FXIa, resulting in the detachment of AptE40-QDs-EK from MNPs-FXIa. After magnetic separation, the enterokinase of AptE40-QDs-EK in the supernatant hydrolyzed N-terminal hexapeptide of trypsinogen, leading to the production of a large amount of trypsin as part of the first-stage signal cascade amplification. Next, trypsin could hydrolyze the hexameric arginine peptide (RRRRRR, R6), leading to the dissociation of RQDs from the R6-RQDs signal probe; this resulted in a dramatic increase in the fluorescence intensity of the supernatant as the second-stage signal cascade was amplified. The feasibility of the method was investigated using the FXIa inhibitor aptamer FELIAP as a positive model drug. Furthermore, the method was applied to screen the FXIa inhibitors in Eupolyphaga sinensis Walker. Two fractions with more active anticoagulated ingredients were successfully identified and validated via the conventional method, and the results were consistent. The established method provides a key technique for the sensitive detection, high-throughput analysis, and screening of the FXIa inhibitors.

The detection of nucleic acid marker is essential for accurate and timely diagnosis and prognosis of different types of diseases. However, the sensitivity and specificity of the assay still need to be improved. Due to the highly ordered porous structure, adjustable pore size, and large specific surface area, metal/covalent-organic frameworks (MOFs/ COFs) can construct multifunctional sensors, which show significant advantages of adsorption, fluorescence quenching/emission, and electrocatalysis in nucleic acid detection. This review provides an overview of the design and construction of biosensors using MOFs/COFs for nucleic acid detection. The interaction between MOFs/COFs and nucleic acids and the detection of ctDNAs, microRNAs, mRNAs, genes, and other nucleic acid molecules based on these biosensors have been comprehensively discussed. In addition, the successful cases proposed by our and other groups have been analyzed in detail. The focus is on the rational design of biosensors by taking advantage of the unique structures and optical properties of MOFs/COFs to improve the sensitivity and selectivity of nucleic acid detection. We hope that the perspectives and insights provided in this review will promote the exploration of further potential applications of MOFs and/or COFs in biomarker sensing and imaging.

Polycyclic aromatic hydrocarbons (PAHs) are a class of ubiquitous and persistent organic compounds that are significantly teratogenic, carcinogenic and mutagenic.

Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control of both the enzyme and its substrate at the target site, preservation of enzyme activity, and in situ substrate depletion due to low prodrug delivery efficiency continue to be great challenges. Here, we propose a novel core–shell reactor partitioning enzyme and prodrug by ZIF-8, which integrates an enzyme with its substrate and increases the drug loading capacity (DLC) using a prodrug as the building ligand to form a Zn-prodrug shell. Cytochrome P450 (CYP450) is immobilized in ZIF-8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer with a high DLC of 43.6±0.8 %. With this configuration, a much higher prodrug conversion efficiency of CYP450 (36.5±1.5 %) and lower IC 50 value (26.3±2.6 μg/mL) are measured for B16-F10 cells with a higher NADPH concentration than those of L02 cells and HUVECs. With the tumor targeting ability of hyaluronic acid, this core–shell enzyme reactor shows a high tumor suppression rate of 96.6±1.9 % and provides a simple and versatile strategy for enabling in vivo biocatalysis to be more efficient, selective, and safer.

建立了测定奈玛特韦原料药绝对含量的定量核磁共振氢谱法(1H qNMR).基于奈玛特韦在溶液中的构象稳定条件,以DMSO-D6和D2O(5∶1,体积比)为溶剂,δ4.96(1H,dd)和δ4.67(1H,dd)处的质子信号作为奈玛特韦的定量峰,δ6.22(1H,t)和δ5.84(1H,d)为拉米夫定的内标峰.样品与内标摩尔比在0.5∶1.0～1.2∶1.0范围时的线性拟合方程为Y=0.456 4X-0.000 5(r2 = 0.999 9),该方法专属性强,耐用性、重复性良好,回收率满足要求,稳定性可达48 h.该方法测得的奈玛特韦样品的含量为99.23%(相对标准偏差为0.24%).1H qNMR法操作简单,具有无损、准确快速的特点,适用于新药奈玛特韦绝对含量的测定.

Drug-target recognition has great impacts on revealing mechanisms of pharmacological activities, especially drug resistance and off-target effects. In recent years, chemoproteomics has been widely used for drug target screening and discovery due to its high-throughput, high accuracy, and sensitivity. However, there still remain challenges on how to efficiently and unambiguously track target proteins from complex biological matrices. Herein, we report a drug target screening method based on virus-like iron-gold heterogeneous nanoparticles (Au@Fe3O4 NPs). The unique structure of Au@Fe3O4 NPs not only maintains the magnetism of Fe3O4 NPs to facilitate protein enrichment and purification, but also increases drug modification by introducing more active sites on the surface of Au NPs. After coincubating the drug modified NPs with the cell lysate, the high loading of drug on the surface of Au@Fe3O4 NPs was beneficial for capturing target proteins with low abundance. This well-designed heterogeneous nanomaterial provides a novel strategy for improving the efficiency and accuracy of affinity-based proteomics.