Computational investigation of the inhibitory interaction of IRF3 and SARS-CoV-2 accessory protein ORF3b.

ORF3b is one of the SARS-CoV-2 accessory proteins. Previous experimental study suggested that ORF3b prevents IRF3 translocating to nucleus. However, the biophysical mechanism of ORF3b-IRF3 interaction is elusive. Here, we explored the conformation ensemble of ORF3b using all-atom replica exchange molecular dynamics simulation. Disordered ORF3b has mixed α-helix, ß-turn and loop conformers. The potential ORF3b-IRF3 binding modes were searched by docking representative ORF3b conformers with IRF3, and 50 ORF3b-IRF3 complex poses were screened using molecular dynamics simulations ranging from 500 to 1000 ns. We found that ORF3b binds IRF3 predominantly on its CBP binding and phosphorylated pLxIS motifs, with CBP binding site has the highest binding affinity. The ORF3b-IRF3 binding residues are highly conserved in SARS-CoV-2. Our results provided biophysics insights into ORF3b-IRF3 interaction and explained its interferon antagonism mechanism.

Simulation-Guided Rational Design of DNA Walker-Based Theranostic Platform.

Biomolecule-functionalized nanoparticles represent a type of promising biomaterials in biomedical applications owing to their excellent biocompatibility and versatility. DNA-based reactions on nanoparticles have enabled emerging applications including intelligent biosensors, drug delivery, and biomimetic devices. Among the reactions, strand hybridization is the critical step to control the sensitivity and specificity of biosensing, and the efficiency of drug delivery. However, a comprehensive understanding of DNA hybridization on nanoparticles is still lacking, which may differ from the process in homogeneous solutions. To address this limitation, coarse-grained model-based molecular dynamic simulation is harnessed to disclose the critical factors involved in intermolecular hybridization. Based on simulation guidance, DNA walker-based smart theranostic platform (DWTP) based on "on-particle" hybridization is developed, showing excellent consistency with simulation. DWTP is successfully applied for highly sensitive miRNA 21 detection and tumor-specific miRNA 21 imaging, driven by tumor-endogenous APE 1 enzyme. It enables the precise release of antisense oligonucleotide triggered by tumor-endogenous dual-switch miRNA 21 and APE 1, facilitating effective gene silencing therapy with high biosafety. The simulation of "on-particle" DNA hybridization has improved the corresponding biosensing performance and the release efficiency of therapeutic agents, representing a conceptually new approach for DNA-based device design.

Multiplexed CRISPR-Based Nucleic Acid Detection Using a Single Cas Protein.

Thanks to its ease, speed, and sensitivity, CRISPR-based nucleic acid detection has been increasingly explored for molecular diagnostics. However, one of its major limitations is lack of multiplexing capability because the detection relies on the trans-cleavage activity of the Cas protein, which necessitates the use of multiple orthogonal Cas proteins for multiplex detection. Here we report the development of a multiplexed CRISPR-based nucleic acid detection system with single-nucleotide resolution using a single Cas protein (Cas12a). This method, termed as CRISPR-TMSD, integrates the toehold-mediated strand displacement (TMSD) reaction, and the cis-cleavage activity of the Cas protein and multiplexed detection are achieved using a single Cas protein owing to the use of target-specific reporters. A set of computational simulation toolkits was used to design the TMSD reporter, allowing for highly sensitive and specific identification of target sequences. In combination with the recombinase polymerase amplification (RPA), the detection limit can reach as low as 1 copy/µL. As proof of concept, CRISPR-TMSD was subsequently used to detect an oncogenic gene and SARS-CoV-2 RNA with a single-nucleotide resolution. This work represents a conceptually new strategy for designing a CRISPR-based diagnostic system and has great potential to expand the application of CRISPR-based diagnostics.

Nanozyme-Based Colorimetric SARS-CoV-2 Nucleic Acid Detection by Naked Eye.

Fluorescence-based PCR and other amplification methods have been used for SARS-CoV-2 diagnostics, however, it requires costly fluorescence detectors and probes limiting deploying large-scale screening. Here, a cut-price colorimetric method for SARS-CoV-2 RNA detection by iron manganese silicate nanozyme (IMSN) is established. IMSN catalyzes the oxidation of chromogenic substrates by its peroxidase (POD)-like activity, which is effectively inhibited by pyrophosphate ions (PPi). Due to the large number of PPi generated by amplification processes, SARS-CoV-2 RNA can be detected by a colorimetric readout visible to the naked eye, with the detection limit of 240 copies mL-1 . This conceptually new method has been successfully applied to correctly distinguish positive and negative oropharyngeal swab samples of COVID-19. Colorimetric assay provides a low-cost and instrumental-free solution for nucleic acid detection, which holds great potential for facilitating virus surveillance.

Recent advances in aptamer-based biosensors for potassium detection.

Maintaining a stable level of potassium is crucial for proper bodily function because even a slight imbalance can result in serious disorders like hyperkalemia and hypokalemia. Therefore, detecting and monitoring potassium ion (K+) levels are of utmost importance. Various biosensors have been developed for rapid K+ detection, with aptamer-based biosensors garnering significant attention due to their high sensitivity and specificity. This review focuses on aptamer-based biosensors for K+ detection, providing an overview of their signal generation strategies, including electrochemical, field-effect transistor, nanopore, colorimetric, and fluorescent systems. The analytical performance of these biosensors is evaluated comprehensively. In addition, factors that affect their efficiency, such as their physicochemical properties, regeneration for reusability, and linkers/spacers, are listed. Lastly, this review examines the major challenges faced by aptamer-based biosensors in K+ detection and discusses potential future developments.

Simulation-Assisted Localized DNA Logical Circuits for Cancer Biomarkers Detection and Imaging.

DNA-based nanodevices equipped with localized modules have been promising probes for biomarker detection. Such devices heavily rely on the intramolecular hybridization reaction. However, there is a lack of mechanistic insights into this reaction that limits the sensing speed and sensitivity. A coarse-grained model is utilized to simulate the intramolecular hybridization of localized DNA circuits (LDCs) not only optimizing the performance, but also providing mechanistic insights into the hybridization reaction. The simulation guided-LDCs enable the detection of multiple biomarkers with high sensitivity and rapid speed showing good consistency with the simulation. Fluorescence assays demonstrate that the simulation-guided LDC shows an enhanced sensitivity up to 9.3 times higher than that of the same probes without localization. The detection limits of ATP, miRNA, and APE1 reach 0.14 mM, 0.68 pM, and 0.0074 U mL-1 , respectively. The selected LDC is operated in live cells with good success in simultaneously detecting the biomarkers and discriminating between cancer cells and normal cells. LDC is successfully applied to detect the biomarkers in cancer tissues from patients, allowing the discrimination of cancer/adjacent/normal tissues. This work herein presents a design workflow for DNA nanodevices holding great potential for expanding the applications of DNA nanotechnology in diagnostics and therapeutics.

Size, shape and orientation of macro-sized substrate protrusions affect the toe and foot adhesion of geckos.

Geckos are excellent climbers using compliant, hierarchically arranged adhesive toes to negotiate diverse terrains varying in roughness at multiple size scales. Here, we complement advancements at smaller size scales with measurements at the macro scale. We studied the attachment of a single toe and whole foot of geckos on macroscale rough substrates by pulling them along, across and off smooth rods and spheres mimicking different geometric protrusions of substrates. When we pulled a single toe along rods, the force increased with the rod diameter, whereas the attachment force of dragging toes across rods increased from about 60% on small diameter rods relative to a flat surface to ∼100% on larger diameter rods, but showed no further increase as rod diameter doubled. Toe force also increased as the pulling changed from along-rod loading to across-rod loading. When toes were pulled off spheres, the force increased with increasing sphere diameter as observed for along-rod pulling. For feet with separated toes, attachment on spheres was stronger than that on rods with the same diameter. Attachment force of a foot decreased as rod and sphere size increased but remained sufficient to support the body weight of geckos. These results provide a bridge to the macroscale roughness seen in nature by revealing the importance of the dimension, shape and orientation of macroscale substrate features for compliant toe and foot function of geckos. Our data not only enhance our understanding of geckos' environmental adaptive adhesion but can also provide inspiration for novel robot feet in development.

Strict mathematical model of mechanical stress birefringence for optical plates.

The mechanical stress birefringence (SBR) has received attention due to its effect on polarization in immersion lithography. In this paper, we present a strict mathematical model to obtain the correct SBR and slow-axis distributions of optical plates. First, the linear conditions of the model are solved to ensure the reasonable assembly of optical plates. Then we strictly define the plane principal stresses and slow-axis angle, and we give the correct expressions. Utilizing this model, we simulate a transmissivity variable plate, which is divided into 11 layers to obtain the effective SBR experienced by incident light crossing the plate. In this case, the simulation results achieve convergence. The validity of the model is verified by comparing the SBR and slow-axis distributions obtained by different expressions of the plate. This model is of great significance for polarization analysis in lithography systems and the reasonable assembly of optical elements.

Evaluation and comparison of tympanoplasty efficacy with tympanic membrane perforation after chronic suppurative otitis media in dry ear with different microorganisms.

OBJECTIVE: To investigate the distribution of pathogenic bacteria in patients with tympanic membrane perforation after chronic suppurative otitis media (CSOM) in dry ear and its influence on the success rate of tympanoplasty and postoperative infection. METHODS: 740 patients with tympanic membrane perforation after CSOM underwent endoscopic tympanoplasty were selected. The mucosal surface secretion of middle-ear was collected for bacterial culture and drug sensitivity test. The patients were followed up several times from 1 week to 3 months after the surgery. RESULTS: 740 cases of ear secretions samples, raise the pathogens of 208 cases (28.1%), the success rate of surgery with microorganism grown and with no grown was 93.8% and 91.5%. fungus (14.6%) was the most species among the patients with the positive result, followed by methicillin-sensitive Staphylococcus aureus (4.1%), Pseudomonas (2.0%), Staphylococcus epidermidis (1.9%), methicillin-resistant Staphylococcus aureus (1.6%) and so on. There was no statistical difference in the proportion of perforation and infection in each group. There were no statistically significant differences in gender, age and duration of disease among the groups. CONCLUSION: There were still microbial colonization in patients with tympanic membrane perforation after CSOM in dry ear, include fungus, Staphylococcus aureus and Pseudomonas aeruginosa. Different microbial colonization had no influence on the success rate of tympanoplasty and postoperative infection.

Rational Design of DNA Framework-Based Hybrid Nanomaterials for Anticancer Drug Delivery.

Engineered DNA frameworks have been extensively exploited as affinity scaffolds for drug delivery. However, few studies focus on the rational design to comprehensively improve their stability, internalization kinetics, and drug loading efficiency. Herein, DNA framework-based hybrid nanomaterials are rationally engineered by using a molecular docking tool, where the framework acts as a template to support conjugated polymers. The hybrid materials exhibit high stability in biofluids owning to the multiple interactions between DNA and cationic conjugated polymer. Through molecular docking, it is found that a specific structure of the conjugated polymer at major grooves of DNA gives rise to a unique pocket for small-molecular drug doxorubicin (DOX) yielding lower binding energy than conventional DOX binding sites. This increases the binding affinity of DOX, allowing for high drug loading content and efficiency, and preventing drug leakage under physiological condition. As a proof of concept, the hybrid nanomaterials equipped with aptamer are used to carry DOX and antisense oligonucleotide G3139, which effectively inhibits solid tumor growth and shows negligible side effects on mice. It is anticipated that this approach would find broad applications in hybrid materials design and precise medicine.

Establishment and application of a method for screening the therapeutic drugs of ethanol-induced liver injury based on cellular metabonomics.

A drug-screening method to test the capacity of drugs to protect against ethanol-induced liver injury based on cellular metabonomics was established and applied in this study. It screens for the ability to protect against ethanol-induced liver injury by considering changes in the cellular metabolites of human normal liver L-02 cells subjected to ethanol treatment. This method considers cellular metabolites as the main analytical index, principal component analysis and orthogonal partial least squares discriminant analysis as the main multi- and megavariate data analysis methods, and vitamin C as the standard substance to determine the ability to protect against ethanol-induced liver injury. Ability to protect against ethanol-induced liver injury unit = [190 - 50× (14.318 - 10 × Y predictive value)1/2 ] × ability 1 µg/mL vitamin C. Olive leaf extract, Lycium barbarum L extract and fish roe peptide were screened using the established methods. Olive leaf OP phase had the strongest ability to protect against ethanol-induced liver injury, at 81.88. The value for L. barbarum L was 37.56. The fish roe peptide water phase was 63.07. All three have the ability to protect against ethanol-induced liver injury. The drug-screening method for ability to protect against ethanol-induced liver injury based on cell metabonomics is a fast, accurate and effective method for quantitative detection of ability to protect against ethanol-induced liver injury.

A non-equilibrium dissipation system with tunable molecular fuel flux.

Cells convert macromolecule fuel into small molecule fuel through energy pathways, including glycolysis, the citric acid cycle, and oxidative phosphorylation. These processes drive vital dissipative networks or structures. Distinct from direct fuel (DF) utilization (directly acquire and utilize small molecule fuel), this macromolecule fuel mechanism is referred to as indirect fuel (IF) utilization, wherein the generation rate of small molecule fuel (fuel flux) can be effectively regulated. Here, we reported a bionic dissipation system with tunable fuel flux based on dynamic DNA nanotechnology. By regulating the rates of strand displacement and enzymatic reactions, we controlled the fuel flux and further tuned the strength of non-equilibrium transient states. Interestingly, we found that within a certain range, the fuel flux was positively correlated with the strength of the transient state. Once saturation was reached, it became negatively correlated. An appropriate fuel flux supports the maintenance of high-intensity non-equilibrium transients. Furthermore, we harnessed the dissipation system with tunable molecular fuel flux to regulate the dynamic assembly and disassembly of AuNPs. Different fuel fluxes resulted in varying assembly and disassembly rates and strengths for AuNPs, accomplishing a biomimetic process of regulating microtubule assembly through the control of fuel flux within living organisms. This work demonstrated a dissipation system with tunable molecular fuel flux, and we envision that this system holds significant potential for development in various fields such as biomimetics, synthetic biology, smart materials, biosensing, and artificial cells.

Coarse-grained model simulation-guided localized DNA signal amplification probe for miRNA detection.

DNA-based enzyme-free signal amplification strategies are widely employed to detect biomarkers in low abundance. To enhance signal amplification, localized DNA reaction units which increases molecular collision probability is commonly utilized. However, the current understanding of the structure-function relationships in localized DNA signal amplification probes is limited, leading to unsatisfied performance. In this study, we introduced a coarse-grained molecular model to simulate the dynamic behavior of two DNA reaction units within a DNA enzyme-free signal amplification circuit called Localized Catalytic Hairpin Assembly (LCHA). We investigated the impact of localized distance and flexibility on reaction performance. The most efficient LCHA probe guided by simulation exhibits sensitivity 28 times greater that of free CHA, with a detection limit of miR-21 reaching 16 pM, while the least effective LCHA probe demonstrated a modest improvement of only 7 times. We successfully employed the optimized probe to differentiate cancer cells from normal cells based on their miR-21 expression levels, showcasing its quantification ability. By elucidating the mechanistic insights and structure-function relationship in our work, we aim to contribute valuable information that can save users' time and reduce costs when designing localized DNA probes. With a comprehensive understanding of how the localization affects probe performance, researchers can now make more informed and efficient decisions during the design process. This work would find broad applications of DNA nanotechnology in biosensing, biocomputing, and bionic robots.

Intergenerational Integration in Community Building to Improve the Mental Health of Residents-A Case Study of Public Space.

This study defined intergenerational integration in communities at a theoretical level and verified whether a series of measures could facilitate negotiation and communication between community residents and other stakeholders to generate a positive and healthy community environment and gradually improve intergroup relations. Specifically, we applied community psychology and used Hongqiao New Village in Shanghai, China, as a research site to explore intergenerational conflict in public community spaces. The research was divided into two stages: an input stage and an output stage. In the input stage, participatory research and tea parties were used to deeply explore residents' public space requirements. In the output stage, we tested the validity of the theory by using the Intergenerational Attitude Scale to investigate whether the intergenerational relationships were changed by the co-creation intervention. The results showed that the intervention caused a decrease in the incidence of conflict between residents using the square and caused some children to join the older groups in their activities. We thus propose a theoretical system model of intergenerational integration strategies that incorporates elements of integration, disagreement, and synergy in intergenerational interactions. Overall, this paper provides new ideas for building a community environment that supports mental health and improves intergenerational relationships and social well-being.

Histone methylation readers MRG1/MRG2 interact with the transcription factor TCP14 to positively modulate cytokinin sensitivity in Arabidopsis.

Cytokinins influence many aspects of plant growth and development. Although cytokinin biosynthesis and signaling have been well studied in planta, little is known about the regulatory effects of epigenetic modifications on the cytokinin response. Here, we reveal that mutations to Morf Related Gene (MRG) proteins MRG1/MRG2, which are readers of trimethylated histone H3 lysine 4 and lysine 36 (H3K4me3 and H3K36me3), result in cytokinin hyposensitivity during various developmental processes, including callus induction and root and seedling growth inhibition. Similar to the mrg1 mrg2 mutant, plants with a defective AtTCP14, which belongs to the TEOSINTE BRANCHED, CYCLOIDEA, AND PROLIFERATING CELL FACTOR (TCP) transcription factor family, are insensitive to cytokinin. Furthermore, the transcription of several genes related to cytokinin signaling pathway is altered. Specifically, the expression of Arabidopsis thalianaHISTIDINE-CONTAINING PHOSPHOTRANSMITTER PROTEIN 2 (AHP2) decreases significantly in the mrg1 mrg2 and tcp14-2 mutants. We also confirm the interaction between MRG2 and TCP14 in vitro and in vivo. Thus, MRG2 and TCP14 can be recruited to AHP2 after recognizing H3K4me3/H3K36me3 markers and promote the histone-4 lysine-5 acetylation to further enhance AHP2 expression. In summary, our research elucidate a previously unknown mechanism mediating the effects of MRG proteins on the magnitude of the cytokinin response.

Enhanced DNA Entropy-Driven Circuit by Locked Nucleic Acids and Simulation-Guided Localization.

Signal amplification methods based on DNA molecular interactions are promising tools for detecting various biomarkers in low abundance. The entropy-driven circuit (EDC), as an enzyme-free signal amplification method, has been used in detecting and imaging a variety of biomarkers. The localization strategy can effectively increase the local concentration of the DNA reaction modules to improve the signal amplification effect. However, the localization strategy may also amplify the leak reaction of the EDC, and effective signal amplification can be limited by the unclear structure-function relationship. Herein, we utilized locked nucleic acid (LNA) modification to enhance the stability of the localized entropy-driven circuit (LEDC), which suppressed a 94.6% leak signal. The coarse-grained model molecular simulation was used to guide the structure design of the LEDC, and the influence of critical factors such as the localized distance and spacer length was analyzed at the molecular level to obtain the best reaction performance. The sensitivities of miR-21 and miR-141 detected by a simulation-guided optimal LEDC probe were 17.45 and 65 pM, 1345 and 521 times higher than free-EDC, respectively. The LEDC was further employed for the fluorescence imaging of miRNA in cancer cells, showing excellent specificity and sensitivity. This work utilizes LNA and molecular simulations to comprehensively improve the performance of a localized DNA signal amplification circuit, providing an advanced DNA probe design strategy for biosensing and imaging as well as valuable information for the designers of DNA-based probes.

Screening and application of inhibitory aptamers for DNA repair protein apurinic/apyrimidinic endonuclease 1.

The base excision repair (BER) pathway is crucial for DNA repair, and apurinic/apyrimidinic endonuclease 1 (APE1) is a critical enzyme in this pathway. Overexpression of APE1 has been linked to multidrug resistance in various cancers, including lung cancer, colorectal cancer, and other malignant tumors. Therefore, reducing APE1 activity is desirable to improve cancer treatment. Inhibitory aptamers, which are versatile oligonucleotides for protein recognition and function restriction, are a promising tool for this purpose. In this study, we developed an inhibitory aptamer for APE1 using systematic evolution of ligands by exponential (SELEX) technology. We used carboxyl magnetic beads as the carrier and APE1 with a His-Tag as the positive screening target, while the His-Tag itself served as the negative screening target. The aptamer APT-D1 was selected based on its high binding affinity for APE1, with a dissociation constant (Kd) of 1.306 ± 0.1418 nM. Gel electrophoresis analysis showed that APT-D1 at a concentration of 1.6 µM could entirely inhibit APE1 with 21 nM. Our results suggest that these aptamers can be utilized for early cancer diagnosis and the treatment, and as an essential tool for studying the function of APE1.

A Neural Coordination Strategy for Attachment and Detachment of a Climbing Robot Inspired by Gecko Locomotion.

Climbing behavior is a superior motion skill that animals have evolved to obtain a more beneficial position in complex natural environments. Compared to animals, current bionic climbing robots are less agile, stable, and energy-efficient. Further, they locomote at a low speed and have poor adaptation to the substrate. One of the key elements that can improve their locomotion efficiency is the active and flexible feet or toes observed in climbing animals. Inspired by the active attachment-detachment behavior of geckos, a hybrid pneumatic-electric-driven climbing robot with active attachment-detachment bionic flexible feet (toes) was developed. Although the introduction of bionic flexible toes can effectively improve the robot's adaptability to the environment, it also poses control challenges, specifically, the realization of attachment-detachment behavior by the mechanics of the feet, the realization of hybrid drive control with different response characteristics, and the interlimb collaboration and limb-foot coordination with a hysteresis effect. Through the analysis of geckos' limbs and foot kinematic behavior during climbing, rhythmic attachment-detachment strategies and coordination behavior between toes and limbs at different inclines were identified. To enable the robot to achieve similar foot attachment-detachment behavior for climbing ability enhancement, we propose a modular neural control framework comprising a central pattern generator module, a post-processing central pattern generation module, a hysteresis delay line module, and an actuator signal conditioning module. Among them, the hysteresis adaptation module helps the bionic flexible toes to achieve variable phase relationships with the motorized joint, thus enabling proper limb-to-foot coordination and interlimb collaboration. The experiments demonstrated that the robot with neural control achieved proper coordination, resulting in a foot with a 285% larger adhesion area than that of a conventional algorithm. In addition, in the plane/arc climbing scenario, the robot with coordination behavior increased by as much as 150%, compared to the incoordinated one owing to its higher adhesion reliability.

Zeolitic imidazolate framework upgrading polyethylene oxide composite electrolyte for high-energy solid-state lithium batteries.

The energy density of solid-state lithium batteries (SSLBs) has been primarily limited by the low ionic conductivity of solid electrolyte and poor interface compatibility between electrolyte and electrodes. Herein, a multifunctional composite solid polymer electrolyte (CSPE) based on polyethylene oxide (PEO) embedded with zeolitic imidazolate framework-8 deposited on carboxymethyl cellulose (ZIF@CMC) is reported. The ZIF@CMC interpenetrated in PEO matrix creates a continuous Li+ conductive network by combining Zn2+ in ZIF with the unsaturated group in PEO to boost the Li+ transport through the PEO chain segment. On the other hand, Zn2+ can bond with bis(trifluoromethane)sulfonimide (TFSI-) anion, thus promoting the dissolution of lithium salt and releasing more lithium ions. This CSPE demonstrates brilliant electrochemical properties, including a high ionic conductivity of 1.8 × 10-4 S cm-1 at room temperature and a wide electrochemical window of 5 V. The integrated LiFePO4/CSPE/Li batteries using 20 wt.% ZIF-8@CMC show excellent reversible capacity of 145.6 mAh g-1 with a capacity retention of 88.95 % after 200 cycles at a high current density of 0.5C. Our study proposed a novel and effective strategy to construct high-performance solid-state lithium batteries.

A supramolecular assembly strategy for hydrophilic drug delivery towards synergistic cancer treatment.

To improve the drug loading, tumor targeting, and delivery simplicity of hydrophilic drugs, we propose a supramolecular assembly strategy that potentially benefits a wide range of hydrophilic drug delivery. Firstly, we choose a hydrophilic drug (tirapazamine) as a model drug to directly co-assemble with chlorin e6 (Ce6) at different molar ratios, and systematically evaluate the resultant Ce6-tirapazamine nanoparticles (CT NPs) in aspects of size distribution, polydispersity, morphology, optical properties and molecular dynamics simulation. Based on the assembling facts between Ce6 and tirapazamine, we summarize a plausible rule of the supramolecular assembly for hydrophilic drugs. To validate our findings, more drugs with increasing hydrophilicity, such as temozolomide, gemcitabine hydrochloride and 5-azacytidine, successfully co-assemble with Ce6 into nanostructures by following similar assembling behaviors, demonstrating that our assembling rule may guide a wide range of hydrophilic drug delivery. Next, the combination of Ce6 and tirapazamine was chosen as the representative to investigate the anti-tumor activities of the supramolecular assemblies. CT NPs showed synergistic anti-tumor efficacy, increased tumor accumulation and significant tumor progression and metastasis inhibition in tumor-bearing mice. We anticipate that the supramolecular assembly mechanism will provide broad guidance for developing easy-to-make but functional nanomedicines. STATEMENT OF SIGNIFICANCE: Although thousands of nanomedicines have been developed, only a few have been approved for clinical use. The manufacturing complexity significantly hinders the "bench-to-bed" translation of nanomedicines. Hence, we need to rethink how to conduct research on translational nanomedicines by avoiding more and more complex chemistry and complicated nanostructures. Here, we summarize a plausible rule according to multiple supramolecular assembly pairs and propose a supramolecular assembly strategy that can improve the drug loading, tumor targeting, and manufacturing simplicity of nanomedicine for hydrophilic drugs. The supramolecular assembly strategy would guide a broader range of drug delivery to provide a new paradigm for developing easy-to-make but multifunctional nanoformulations for synergistic cancer treatment.