Pillarurilarenes: Glycoluril-Expanded Pillararenes.

Glycoluril-expanded pillararenes composed of glycoluril and dialkoxybenzene units, namely, pillarurilarenes (PURA), were synthesized through a fragment coupling macrocyclization strategy. Partial replacement of dialkoxybenzene with glycoluril endows PURA with polarized equatorial methine protons for derivatization or CH-anion binding. Crystal structures of pillar[2]uril[4]arene and pillar[1]uril[4]arene containing two glycoluril units and one glycoluril unit, respectively, indicated the inward orientation of the glycoluril unit, as also suggested by 1H nuclear magnetic resonance and density functional theory calculation. This work lays a good foundation for expanding pillararenes using non-aromatic rings.

Influence of Social Distance on Foreign Language Effect in Moral Judgment.

Previous research has shown that moral choice depends on language, a phenomenon known as the moral foreign language effect (mFLE). The current study examines the influence of social distance on the mFLE. In Experiment 1, 200 participants were randomly assigned to either close or distant social distance in English or Chinese. In Experiment 2, 188 participants were randomly assigned to either English or Chinese and were presented with eight moral dilemmas, each with five different levels of social distance. After reading the dilemma, participants made a choice on a binary scale (Yes/No) in both Experiments 1 and 2 or on a more sensitive 100-point scale in Experiment 2. The results showed that the mFLE was present in distant social distance but absent in close social distance. Finally, a meta-analysis of the results from both studies confirmed the effect of social distance on the mFLE. These findings demonstrate that social distance might play an important role in moderating the mFLE in moral judgment.

Extracellular Vesicles Maintain Blood-Brain Barrier Integrity by the Suppression of Caveolin-1/CD147/VEGFR2/MMP Pathway After Ischemic Stroke.

Background: Ischemic stroke (IS) causes tragic death and disability worldwide. However, effective therapeutic interventions are finite. After IS, blood-brain barrier (BBB) integrity is disrupted, resulting in deteriorating neurological function. As a novel therapeutic, extracellular vesicles (EVs) have shown ideal restorative effects on BBB integrity post-stroke; however, the definite mechanisms remain ambiguous. In the present study, we investigated the curative effects and the mechanisms of EVs derived from bone marrow mesenchymal stem cells and brain endothelial cells (BMSC-EVs and BEC-EVs) on BBB integrity after acute IS. Methods: EVs were isolated from BMSCs and BECs, and we investigated the therapeutic effect in vitro oxygen-glucose deprivation (OGD) insulted BECs model and in vivo rat middle cerebral artery occlusion (MCAo) model. The cell monolayer leakage, tight junction expression, and metalloproteinase (MMP) activity were evaluated, and rat brain infarct volume and neurological function were also analyzed. Results: The administration of two kinds of EVs not only enhanced ZO-1 and Occludin expressions but also reduced the permeability and the activity of MMP-2/9 in OGD-insulted BECs. The amelioration of the cerebral infarction, BBB leakage, neurological function deficits, and the increasing ZO-1 and Occludin levels, as well as MMP activity inhibition was observed in MCAo rats. Additionally, the increased levels of Caveolin-1, CD147, vascular endothelial growth factor receptor 2 (VEGFR2), and vascular endothelial growth factor A (VEGFA) in isolated brain microvessels were downregulated after EVs treatment. In vitro, the employment of Caveolin-1 and CD147 siRNA partly suppressed the expressions of VEGFR2, VEGFA and MMP-2/9 activity and reduced the leakage of OGD insulted BECs and enhanced ZO-1 and Occludin expressions. Conclusion: Our study firstly demonstrates that BEC and BMSC-EVs administrations maintain BBB integrity via the suppression of Caveolin-1/CD147/VEGFR2/MMP pathway after IS, and the efficacy of BMSC-EVs is superior to that of BEC-EVs.

Targeted therapies of inflammatory diseases with intracellularly gelated macrophages in mice and rats.

Membrane-camouflaged nanomedicines often suffer from reduced efficacy caused by membrane protein disintegration and spatial disorder caused by separation and reassembly of membrane fragments during the coating process. Here we show that intracellularly gelated macrophages (GMs) preserve cell membrane structures, including protein content, integration and fluidity, as well as the membrane lipid order. Consequently, in our testing GMs act as cellular sponges to efficiently neutralize various inflammatory cytokines via receptor-ligand interactions, and serve as immune cell-like carriers to selectively bind inflammatory cells in culture medium, even under a flow condition. In a rat model of collagen-induced arthritis, GMs alleviate the joint injury, and suppress the overall arthritis severity. Upon intravenous injection, GMs efficiently accumulate in the inflammatory lungs of acute pneumonia mice for anti-inflammatory therapy. Conveniently, GMs are amenable to lyophilization and can be stored at ambient temperatures for at least 1 month without loss of integrity and bio-activity. This intracellular gelation technology provides a universal platform for targeted inflammation neutralization treatment.

Internal Dynamics and Modular Peripheral Binding in Stimuli-Responsive 3 : 2 Host:Guest Complexes.

Now that the chemistry of 1 : 1 host:guest complexes is well-established, it is surprising to note that higher stoichiometry (oligomeric) complexes, especially those with excess host, remain largely unexplored. Yet, proteins tend to oligomerize, affording new functions for cell machinery. Here, we show that cucurbit[n]uril (CB[n]) macrocycles combined with symmetric, linear di-viologens form unusual 3 : 2 host:guest complexes exhibiting remarkable dynamic properties, host self-sorting, and external ring-translocation. These results highlight the structural tunability of cucurbit[8]uril (CB[8]) based 3 : 2 host:guest complexes in water and their responsiveness toward several stimuli (chemicals, pH, redox).

Protective Effect of Baicalin on Chlorpyrifos-Induced Liver Injury and Its Mechanism.

Chlorpyrifos (CPF) plays a vital role in the control of various pests in agriculture and household life, even though some studies have indicated that CPF residues pose a significant risk to human health. Baicalin (BA) is a flavonoid drug with an obvious effect on the prevention and treatment of liver diseases. In this study, the protective effect of BA in vitro and in vivo was investigated by establishing a CPF-induced AML12 cell damage model and a CPF-induced Kunming female mouse liver injury model. The AML12 cell damage model indicated that BA had a good positive regulatory effect on various inflammatory factors, redox indexes, and abnormal apoptosis factors induced by CPF. The liver injury model of female mice in Kunming showed that BA significantly improved the liver function indexes, inflammatory response, and fibrosis of mice. In addition, BA alleviated CPF-induced AML12 cell damage and Kunming female mouse liver injury by enhancing autophagy and regulating apoptosis pathways through Western blotting. Collectively, these data suggest that the potential mechanism of BA is a multi-target and multi-channel treatment for chlorpyrifos-induced liver injury.

Supramolecularly Engineered Conjugate of Bacteria and Cell Membrane-Coated Magnetic Nanoparticles for Enhanced Ferroptosis and Immunotherapy of Tumors.

Although various ferroptosis inducers including magnetic nanoparticles (Fe3 O4 ) and iron-organic frameworks have been applied in cancer treatment, the mild immunogenicity, low targeting efficiency to the tumor, and poor tissue penetration have limited the therapeutic efficacy. Herein, a supramolecularly engineered conjugate between living bacteria (facultative anaerobic Salmonella typhimurium VNP20009, VNP) and cancer cell membranes-coated Fe3 O4 nanoparticles is developed for improving targeted delivery of Fe3 O4 nanoparticles into the tumor tissue and for synergistic ferroptosis and immunotherapy of tumor. The enhanced ferroptosis induced by both Fe3 O4 nanoparticles and the loaded ferroptosis inducing agent (sulfasalazine (SAS)) effectively inhibits tumor growth and generates immune response via immunogenic cell death (ICD). The colonization of VNP in tumors also induces adaptive immune responses and further promotes ferroptosis. Fundamentally, the supramolecular conjugate of VNP and cell membranes-coated Fe3 O4 can potentiate the therapeutic capability of each other through mutually magnifying the ferroptosis and immunotherapy, resulting in significantly enhanced antitumor effects.

Challenges and Opportunities of Functionalized Cucurbiturils for Biomedical Applications.

Cucurbit[n]uril (CB[n]) macrocycles (especially CB[5] to CB[8]) have shown exceptional attributes since their discovery in 2000. Their stability, water solubility, responsiveness to several stimuli, and remarkable binding properties have enabled a growing number of biological applications. Yet, soon after their discovery, the challenge of their functionalization was set. Nevertheless, after more than two decades, a myriad of CB[n] derivatives has been described, many of them used in cells or in vivo for advanced applications. This perspective summarizes key advances of this burgeoning field and points to the next opportunities and remaining challenges to fully express the potential of these fascinating macrocycles in biology and biomedical sciences.

Enhancement of hemostatic properties of Cyclotella cryptica frustule through genetic manipulation.

BACKGROUND: The silicified cell wall of diatoms, also known as frustule, shows huge potential as an outstanding bio-nanomaterial for hemostatic applications due to its high hemostatic efficiency, good biocompatibility, and ready availability. As the architectural features of the frustule determine its hemostatic performance, it is of great interest to develop an effective method to modify the frustule morphology into desired patterns to further improve hemostatic efficiency. RESULTS: In this study, the gene encoding Silicalemma Associated Protein 2 (a silicalemma-spanning protein) of Cyclotella cryptica (CcSAP2) was identified as a key gene in frustule morphogenesis. Thus, it was overexpressed and knocked down, respectively. The frustule of the overexpress lines showed no obvious alteration in morphology compared to the wild type (WT), while the size, specific surface area (BET), pore volume, and pore diameter of the knockdown strains changed greatly. Particularly, the knockdown frustules achieved a more pronounced coagulation effect and in vivo hemostatic performance than the WT strains. Such observations suggested that silicalemma proteins are ideal genetic encoding targets for manipulating frustule morphology associated hemostatic properties. Furthermore, the Mantel test was adopted to identify the key morphologies associated with C. cryptica bleeding control. Finally, based on our results and recent advances, the mechanism of frustule morphogenesis was discussed. CONCLUSION: This study explores a new strategy for enhancing the hemostatic efficiency of the frustule based on genetic morphology modification and may provide insights into a better understanding of the frustule morphogenesis mechanism.

"Ice and Fire" Supramolecular Cell-Conjugation Drug Delivery Platform for Deep Tumor Ablation and Boosted Antitumor Immunity.

Cancer recurrence and metastasis are two major challenges in the current clinical therapy. In this work, a novel diketopyrrolopyrrole-based photothermal reagent (DCN) with unique J-aggregation-induced redshift is synthesized to achieve efficient tumor thermal ablation under safe power (0.33 W cm-2 ). Meanwhile, S-nitroso-N-acetylpenicillamine (SNAP) is co-loaded with near-infrared-absorbing DCN in amphiphilic polymers to realize heat-induced massive release of nitric oxide (NO), which can form oxidant peroxynitrite (ONOO- ) to active matrix metalloproteinases (MMPs), thereby degrading the compact tumor extracellular matrix to improve the ablation depth and infiltration of immune cells. Through a facile supramolecular assembly method, the DCN/SNAP nanoparticles are anchored to liquid-nitrogen-frozen cancer cells, achieving enhanced antitumor immune responses and effective inhibition of distant tumors and pulmonary metastases after only one treatment. The safety and effectiveness of this supramolecular cell-conjugation platform are verified by 2D/3D cellular experiments and bilateral tumor model, confirming the thermal-ablation-gas-permeation-antigen-presentation therapeutic mode has promising anticancer prospects.

The neuropathological mechanism of EV-A71 infection attributes to inflammatory pryoptosis and viral replication via activating the hsa_circ_0045431/ hsa_miR_584/NLRP3 regulatory axis.

Neuropathological damage has been considered to be the main cause of death from EV-A71 infection, but the underlying mechanism has not been elucidated. Pyroptosis, a new form of inflammatory programmed cell death, has been verified to be involved in the pathogenesis of various viruses. circRNAs are a novel type of endogenous noncoding RNA gaining research interest in recent years, especially their special roles in the process of virus infection. Thus, in this study, we combined EV-A71, pyroptosis and circRNA to find a breakthrough in the pathogenesis of EV-A71 infection. Firstly, whether EV-A71 infection leaded to pyroptosis formation was examined by a series detection of cell death, cell viability, LDH release, caspase 1 activity, the expression levels of pyroptosis-related molecules and the concentrations of IL-1ß and IL-18. Secondly, high-throughput sequencing of circRNAs was carried out to excavate the circRNA-miRNA-mRNA regulatory axis which might be associated with pyroptosis formation. Finally, the gain- and loss-of-functional experiments were further conducted to identify their functions. Our results showed that EV-A71 infection caused pyroptosis formation in SH-SY5Y cells. The circRNA sequencing analyzed the differentially expressed circRNAs and their possible functions. It was found that the hsa_circ_0045431/hsa_miR_584/NLRP3 regulatory axis might be involved in pyroptosis formation during EV-A71 infection. Then, hsa_circ_0045431 sponged hsa_miR_584 and hsa_miR_584 directly targeted NLRP3 were validated by IF, dual-luciferase, qRT-PCR and WB assays. Functional experiments were performed to further uncover that the up-regulation of hsa_circ_0045431 and NLRP3 promoted the inflammatory pyroptosis and viral replication, while the up-regulation of hsa_miR_584 suppressed the inflammatory pyroptosis and viral replication, and vice versa. Collectively, our study demystified that EV-A71 infection induced pyroptosis formation by activating hsa_circ_0045431/hsa_miR_584/NLRP3 regulatory axis, which could further effect viral replication. These findings provided novel insights into the pathogenesis of EV-A71 infection, and meanwhile revealed that the hsa_circ_0045431/ hsa_miR_584/NLRP3 regulatory axis can serve as a potential biological therapeutic target for EV-A71 infection.

Synthesis of Bacteria-mimetic Gold Nanoparticles for Phagocytosis by Immune Cells.

Cell-based carrier exhibits inherent advantages as the next generation of drug delivery system, namely high biocompatibility and physiological function. Current cell-based carriers are constructed via direct payload internalization or conjugation between cell and payload. However, the cells involved in these strategies must be firstly extracted from the body and the cell-based carrier must be prepared in vitro. Herein, we synthesize bacteria-mimetic gold nanoparticles (GNPs) for the construction of cell-based carrier in mice. Both ß-cyclodextrin (ß-CD)-modified GNPs and adamantane (ADA)-modified GNPs are coated by E. coli outer membrane vesicles (OMVs). The E. coli OMVs induce the phagocytosis of GNPs by circulating immune cells, leading to intracellular degradation of OMVs and subsequent supramolecular self-assembly of GNPs driven by ß-CD-ADA host-guest interactions. In vivo construction of cell-based carrier based on bacteria-mimetic GNPs avoids the immunogenicity induced by allogeneic cells and restriction by the number of separated cells. Due to the inflammatory tropism, endogenous immune cells carry the intracellular GNP aggregates to the tumor tissues in vivo. Graphical overview Collect the outer membrane vesicles (OMVs) of E. coli by gradient centrifugation (a) and coat on gold nanoparticles (GNP) surface (b) to prepare OMV-coated cyclodextrin (CD)-GNPs and OMV-coated adamantane (ADA)-GNPs (c) via ultrasonic method.

"Zombie" Macrophages for Targeted Drug Delivery to Treat Acute Pneumonia.

A cell-based drug delivery system has emerged as a promising drug delivery platform. Due to their innate inflammatory tropism, natural and engineered macrophages have exhibited targeted accumulation in inflammatory tissues, which has allowed targeted delivery of medicine for the treatment of a variety of inflammatory diseases. Nevertheless, live macrophages may take up the medicine and metabolize it during preparation, storage, and in vivo delivery, sometimes causing unsatisfactory therapeutic efficacy. In addition, live macrophage-based drug delivery systems are usually freshly prepared and injected, due to the poor stability that does not allow storage. "Off-the-shelf" products would be indeed conducive to the timely therapy of acute diseases. Herein, a cryo-shocked macrophage-based drug delivery system was developed via supramolecular conjugation of cyclodextrin (CD)-modified "zombie" macrophages and adamantane (ADA)-functionalized nanomedicine. "Zombie" macrophages exhibited a much better storage stability over time than their counterpart live macrophage drug carriers and maintained cell morphology, membrane integrity, and biological functions. In an acute pneumonia mouse model, "zombie" macrophages carried quercetin-loaded nanomedicine, hand-in-hand, to the inflammatory lung tissues and effectively alleviated the inflammation in mice.

Platelet-mimicking supramolecular nanomedicine with precisely integrated prodrugs for cascade amplification of synergistic chemotherapy.

Camptothecin (CPT) and cisplatin (Pt) have shown synergistic effects on a variety of cancers during preclinical and clinical studies. However, the ratio of the two drugs often could not be precisely regulated in different delivery systems, which hinders the desired synergistic effect. In addition, the low delivery efficiency of the two drugs to the tumor further impedes the ideal therapeutic outcomes. Herein, we report that a platelet-mimicking supramolecular nanomedicine (SN) could precisely control of the ratio of CPT and Pt with a high tumor accumulation rate for cascade amplification of synergistic chemotherapy. The SN was fabricated via the host-guest interaction between cucurbit[7]uril conjugated hyaluronic acid (HA-CB[7]) and adamantane (ADA) respectively functionalized CPT- and Pt-based prodrugs. The ratio of CPT and Pt in the SN could be facilely regulated by simply controlling the loading ratio, based on the strong binding affinity between CB[7] and ADA, and SN60 with 60% CPT and 40% Pt showed the highest synergistic effects on 4T1 cells. To improve the tumor accumulation efficiency of SN, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a tumor vasculature-disruptive agent) was loaded into the optimized SN and then coated with platelet membrane to yield platelet-mimicking supramolecular nanomedicine (D@SN-P). D@SN-P could first passively accumulate in tumors owing to the enhanced permeability and retention (EPR) effect after intravenous administration. The initially release of DMXAA from D@SN-P could induce tumor vascular disruption, and the resultant epithelial collagen exposure around the disrupted tumor vasculature provided a target for further recruitment of platelet-mimicking SN, leading to cascade amplification of tumor accumulation with synergistic chemotherapy. Hence, this platelet-mimicking supramolecular nanomedicine presents a universal supramolecular strategy to finely regulate the ratio of loaded pro-drugs, and improve the accumulation efficiency to amplify chemotherapy via platelet-mimics.

Mitochondria-Targeting Multifunctional Fluorescent Probe toward Polarity, Viscosity, and ONOO- and Cell Imaging.

Abnormal changes occurring in the mitochondrial microenvironment are important markers indicating mitochondrial and cell dysfunction. Herein, we designed and synthesized a multifunctional fluorescent probe DPB that responds to polarity, viscosity, and peroxynitrite (ONOO-). DPB is composed of an electron donor (diethylamine group) and electron acceptor (coumarin, pyridine cations, and phenylboronic acid esters), in which the pyridine group with a positive charge is responsible for targeting to mitochondria. D-π-A structure with strong intramolecular charge transfer (ICT) and twisted intramolecular charge transfer (TICT) properties give rise to respond to polarity and viscosity. The introduction of cyanogroup and phenylboronic acid esters increases the electrophilicity of the probe, which is prone to oxidation triggered by ONOO-. The integrated architecture satisfies the multiple response requirements. As the polarity increases, the fluorescence intensity of probe DPB at 470 nm is quenched by 97%. At 658 nm, the fluorescence intensity of DPB increases with viscosity and decreases with the concentration of ONOO-. Furthermore, the probe is not only successfully used to monitor mitochondrial polarity, viscosity, and endogenous/exogenous ONOO- level fluctuations but also to distinguish cancer cells from normal cells by multiple parameters. Therefore, as-prepared probe provides a reliable tool for better understanding of the mitochondrial microenvironment and also a potential approach for the diagnosis of disease.

Microalgae Microneedle Supplies Oxygen for Antiphotoaging Treatment.

UV exposure often triggers photoaging of the skin. Pharmacological treatment suffers from severe side effects as well as poor efficacy because of insufficient skin penetration. Dissolved oxygen has been previously shown to reverse photoaged skin; however, the treatment is often limited by the availability of equipment (e.g., high-pressure oxygen). Poor oxygen diffusion into the skin has also limited its therapeutic efficacy. Herein, we developed a microneedle patch to deliver living microalgae to the deeper layers of the skin for efficient oxygenation and reversal of photoaging. The continuous release of oxygen from microalgae in the skin through photosynthesis reversed the inflammatory microenvironment and reduced reactive oxygen species levels in the photodamaged skin, leading to collagen regeneration and reduced wrinkles. This study provides not only a means for highly efficient skin oxygenation and reversal of photoaging but also an important theoretical basis for the clinical treatment of photoaging.

Network pharmacology and molecular docking analysis on the mechanism of Cordyceps militaris polysaccharide regulating immunity through TLR4/TNF-α pathwayss.

The role of polysaccharide components in the immune system, especially immunomodulatory effects, has received increasing attention. In this context, in this study, network pharmacology was adopted to explore the hypothesis of a multitarget mechanism for immune modulation by Chrysalis polysaccharides. A total of 174 common targets were screened by network pharmacology, with the main ones being TNF, MAPK3, CASP3, VEGFA, and STAT3, mostly enriched in the Toll pathway. The molecular docking results showed that the polysaccharide fraction of Chrysalis binds well to TNF proteins. Besides, in vitro cellular assays were performed to verify the ability of Chrysalis polysaccharides to regulate macrophage polarization and to screen for macrophage surface receptors. Furthermore, in vivo experiments were conducted to prove the activation of TLR4 and TNF-α protein expression in mice by Chrysalis polysaccharide.

Drug-free tumor therapy via spermine-responsive intracellular biomineralization.

Chemotherapy based on molecular drugs remains the most frequently used approach for the therapy of tumors, however their poor specificity, severe side effects and tumor resistance often seriously hinder their applications. It is therefore desirable to develop a new, alternative therapeutic strategy for tumor treatment without traditional chemotherapeutic drugs. Herein, we report a drug-free tumor therapy approach involving spermine (SPM)-responsive intracellular biomineralization in tumor cells. In this work, we designed calcium carbonate (CaCO3) nanoparticles capped with folic acid and supramolecular peptides, which could target tumor cells and rapidly self-aggregate into micron-sized CaCO3 aggregates in SPM-overexpressed tumor cells. Due to the extended intracellular retention, CaCO3 aggregates could induce intracellular biomineralization and Ca2+ overload of tumor cell, leading to mitochondrial damage and cellular apoptosis, resulting in effective inhibition of tumor growth without serious side effects otherwise seen in conventional chemotherapy.

Bacteria-mimetic nanomedicine for targeted eradication of intracellular MRSA.

Drug-resistant infections caused by intracellular bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), which are often hidden inside macrophages, pose a significant threat to human health. Various nanomedicines have been developed to combat intracellular MRSA; however, their poor uptake and fast clearance from macrophages often result in insufficient enrichment of antibacterial agents intracellularly, leading to low antibacterial efficacy. Here, we developed bacterial membrane-coated mesoporous SiO2 nanoparticles (MSN) loaded with vancomycin (Van), a classic antibiotic. These nanoparticles can be specifically recognized and internalized by macrophages and self-aggregated into micron-sized MSN clusters based on cucurbit[7]uril-adamantane host-guest interactions, allowing for slow clearance and extended retention in infected macrophages. The acid-triggered, sustainable release of Van from MSN aggregates effectively killed MRSA in infected macrophages and significantly alleviated inflammation caused by intracellular bacterial infections both in vitro and in vivo. This work not only provides a practical solution to effectively treat drug-resistant intracellular infections but also offers new insights for the design and development of antibacterial nanomaterials.

Hyaluronic acid-based supramolecular nanomedicine with optimized ratio of oxaliplatin/chlorin e6 for combined chemotherapy and O2-economized photodynamic therapy.

Dual- or multi-modality combination therapy has become one of the most effective strategies to overcome drug resistance in cancer therapy, and the optimized ratio of the therapeutic agents working on the tumor greatly affects the therapeutic outcomes. However, the absence of a facile method to optimize the ratio of therapeutic agents in nanomedicine has, at least in part, impaired the clinical potential of combination therapy. Herein, a new cucurbit[7]uril (CB[7])-conjugated hyaluronic acid (HA) based nanomedicine was developed, in which both chlorin e6 (Ce6) and oxaliplatin (OX) were co-loaded non-covalently at an optimized ratio via facile host-guest complexation, for optimal, combined photodynamic therapy (PDT)/chemotherapy. To maximize the therapeutic efficacy, a mitochondrial respiration inhibitor, atovaquone (Ato), was also loaded into the nanomedicine to limit consumption of oxygen by the solid tumor, sparing oxygen for more efficient PDT. Additionally, HA on the surface of nanomedicine allowed targeted delivery to cancer cells with over-expressed CD44 receptors (such as CT26 cell lines). Thus, this supramolecular nanomedicine platform with an optimal ratio of photosensitizer and chemotherapeutic agent not only provides an important new tool for enhanced PDT/chemotherapy of solid tumors, but also offers a CB[7]-based host-guest complexation strategy to facilely optimize the ratio of therapeutic agents for multi-modality nanomedicine. STATEMENT OF SIGNIFICANCE: Chemotherapy remains the most common modality for cancer treatment in clinical practice. Combination therapy by co-delivery of two or more therapeutic agents has been recognized as one of the most effective strategies to improve therapeutic outcome of cancer treatment. However, the ratio of loaded drugs could not be facilely optimized, which may greatly affect the combination efficiency and overall therapeutic outcome. Herein, we developed a hyaluronic acid based supramolecular nanomedicine with facile method to optimize the ratio of two therapeutic agents for improved therapeutic outcome. This supramolecular nanomedicine not only provides an important new tool for enhanced photodynamic therapy/chemotherapy of solid tumors, but also offers insights in using macrocyclic molecule-based host-guest complexation to facilely optimize the ratio of therapeutic agents in multi-modality nanomedicine.