Macromolecules with predominant ß-pleated sheet proteins in extracellular vesicles released from Raphanus sativus L. var. caudatus Alef microgreens induce DNA damage-mediated apoptosis in HCT116 colon cancer cells.

Plant-derived bioactive macromolecules (i.e., proteins, lipids, and nucleic acids) were prepared as extracellular vesicles (EVs). Plant-derived EVs are gaining pharmaceutical research interest because of their bioactive components and delivery properties. The spherical nanosized EVs derived from Raphanus sativus L. var. caudatus Alef microgreens previously showed antiproliferative activity in HCT116 colon cancer cells from macromolecular compositions (predominantly proteins). To understand the mechanism of action, the biological activity studies, i.e., antiproliferation, cellular biochemical changes, DNA conformational changes, DNA damage, apoptotic nuclear morphological changes, apoptosis induction, and apoptotic pathways, were determined by neutral red uptake assay, synchrotron radiation-based Fourier transform infrared microspectroscopy, circular dichroism spectroscopy, comet assay, 4',6-diamidino-2-phenylindole (DAPI) staining, flow cytometry, and caspase activity assay, respectively. EVs inhibited HCT116 cell growth in concentration- and time-dependent manners, with a half-maximal inhibitory concentration of 675.4 ± 33.8 µg/ml at 48 h and a selectivity index of 1.5 ± 0.076. HCT116 treated with EVs mainly changed the cellular biochemical compositions in the nucleic acids and carbohydrates region. The DNA damage caused no changes in DNA conformation. The apoptotic nuclear morphological changes were associated with the increased apoptotic cell population. The apoptotic cell death was induced by both extrinsic and intrinsic pathways. EVs have potential as antiproliferative bioparticles.

Novel biomimetic macromolecules system for highly efficient lubrication, ROS scavenging and osteoarthritis treatment.

The early stages of osteoarthritis (OA) in the joints are typically characterized by two key factors: the dysfunction of articular cartilage lubrication and inflammation resulting from the excessive production of reactive oxygen species (ROS). Synthetic injectable macromolecular materials present great potential for preventing the progression of early OA. In this study, to mimic the excellent lubricity of brush-like aggregates found in natural synovial fluid, we develop a novel macromolecular biolubricant (CS-PS-DA) by integrating adhesion and hydration groups onto backbone of natural biomacromolecules. CS-PS-DA exhibits a strong affinity for cartilage surfaces, enabling the formation of a stable lubrication layer at the sliding interface of degraded cartilages to restore joint lubrication performance. In vitro results from ROS scavenging and anti-inflammatory experiments indicate the great advantage of CS-PS-DA to decrease the levels of proinflammatory cytokines by inhibiting ROS overproduction. Finally, in vivo rats OA model demonstrates that intra-cavitary injection of CS-PS-DA could effectively resist cartilage wear and mitigated inflammation in the joints. This novel biolubricant provides a new and timely strategy for the treatment of OA.

Advances in natural and synthetic macromolecules with stem cells and extracellular vesicles for orthopedic disease treatment.

Serious orthopedic disorders resulting from myriad diseases and impairments continue to pose a considerable challenge to contemporary clinical care. Owing to its limited regenerative capacity, achieving complete bone tissue regeneration and complete functional restoration has proven challenging with existing treatments. By virtue of cellular regenerative and paracrine pathways, stem cells are extensively utilized in the restoration and regeneration of bone tissue; however, low survival and retention after transplantation severely limit their therapeutic effect. Meanwhile, biomolecule materials provide a delivery platform that improves stem cell survival, increases retention, and enhances therapeutic efficacy. In this review, we present the basic concepts of stem cells and extracellular vesicles from different sources, emphasizing the importance of using appropriate expansion methods and modification strategies. We then review different types of biomolecule materials, focusing on their design strategies. Moreover, we summarize several forms of biomaterial preparation and application strategies as well as current research on biomacromolecule materials loaded with stem cells and extracellular vesicles. Finally, we present the challenges currently impeding their clinical application for the treatment of orthopedic diseases. The article aims to provide researchers with new insights for subsequent investigations.

Synthesis and biological properties of novel glucose-based fluoro segmented macromolecular architectures.

The emergence of novel well-defined biological macromolecular architectures containing fluorine moieties displaying superior functionalities can satisfactorily address many biomedical challenges. In this research, ABA- and AB-type glucose-based biological macromolecules were synthesized using acryl-2,3,4,6-tetra-O-acetyl-D-glucopyranoside with pentafluorophenyl (FPM), pentafluorobenzyl (FBM), phenyl (PM) and benzyl (BM) methacrylate-based macro-RAFT agents following RAFT polymerization. The macro-RAFT agents and the corresponding copolymers were characterized by 19F, 1H, and 13C NMR and FTIR spectroscopic techniques to understand the chemical structure, molecular weight by size-exclusion chromatography, thermal analysis by TGA and DSC. Thermal stability (Td5%) of the FPM and FBM fluoro-based polymers was observed in the range of 219-267 °C, while the non-fluoro PM and BM polymers exhibited in the range of 216-264 °C. Among the macro-RAFT agents, PFPM (107 °C, ΔH: 0.613 J/g) and PPM (103 °C, ΔH: 0.455 J/g) showed higher Tm values, while among the block copolymers, PFBM-b-PG (123 °C, ΔH: 0.412 J/g) and PG-b-PFPM-b-PG (126 °C, ΔH: 0.525 J/g) exhibited higher Tm values. PFBMT and PPM macro-RAFT agents, PPM-b-PG and PG-b-PPM-b-PG copolymer spin-coated films showed the highest hydrophobicity (120°) among the synthesized polymers. The block copolymers exhibited self-assembled segregation by using relatively hydrophobic segments as the core and hydrophilic moieties as the corona. Synthesized biological macromolecules exhibit maximum antibacterial activity towards S. aureus than E. coli bacteria. Fluorophenyl (PFPM) and non-fluorobenzyl-based (PBMT) macro-RAFT agents exhibit low IC50 values, suggesting high cytotoxicity. All the triblock copolymers exhibit lesser cytotoxicity than the di-block polymers.

Modulation of bacterial membranes and cellular macromolecules by dimethyl sulfoxide: A dose-dependent study providing novel insights.

Using Escherichia coli as a model, this manuscript delves into the intricate interactions between dimethyl sulfoxide (DMSO) and membranes, cellular macromolecules, and the effects on various aspects of bacterial physiology. Given DMSO's wide-ranging use as a solvent in microbiology, we investigate the impacts of both non-growth inhibitory (1.0 % and 2.5 % v/v) and slightly growth-inhibitory (5.0 % v/v) concentrations of DMSO. The results demonstrate that DMSO causes alterations in bacterial membrane potential, influences the electrochemical characteristics of the cell surface, and exerts substantial effects on the composition and structure of cellular biomolecules. Genome-wide gene expression data from DMSO-treated E. coli was used to further investigate and bolster the results. The findings of this study provide valuable insights into the complex relationship between DMSO and biological systems, with potential implications in drug delivery and cellular manipulation. However, it is essential to exercise caution when utilizing DMSO to enhance the solubility and delivery of bioactive compounds, as even at low concentrations, DMSO exerts non-inert effects on cellular macromolecules and processes.

Chemical Proteomics and Morphological Profiling Revealing MYDGF as a Target for Synthetic Anticancer Macromolecules.

Biodegradable guanidinium-functionalized polycarbonates kill cancer cells via membrane translocation without causing resistance after repeated use, but the exact molecular targets of the polycarbonates are unknown. Here, we investigate the protein targets of the polycarbonates through affinity-based protein profiling and report myeloid-derived growth factor (MYDGF) as the main protein target. Direct binding of the polycarbonates to MYDGF protein is validated through biolayer interferometry. MYDGF is overexpressed in a range of cancer cells, and knockdown of MYDGF is shown to reduce cell proliferation in cancer cells. Through morphological profiling, we also identify similarities in phenotypic effects of the functionalized polycarbonates with topoisomerase I inhibitors, MDM2 inhibitors, and phosphatidylinositol 3kinase inhibitors against cancer cells, suggesting a common mechanism through the PIK3/AKT pathway leading to apoptosis. These findings present the first macromolecular compound targeting MYDGF and may serve as an example for MYDGF modulation as a potential new target for macromolecular chemotherapeutic development.

Aggregation-Induced Emission Macromolecular Materials for Antibacterial Applications.

Recent advancements in aggregation-induced emission (AIE) macromolecular materials have brought their attention as potential antibacterial solutions, these materials offer new approaches to cure multidrug-resistant infections and biofilms in bacterial infections as well as real-time monitoring and specific targeting of bacteria. This review provides an overview of the three main categories of AIE macromolecular materials with antibacterial properties; namely AIE-active polymers, AIEgen@polymer complexes, and clusterization-triggered emission (CTE) based polymers. The mechanisms and applications of these materials in antibacterial treatment, wound care, and protective equipment are also discussed. The potential for future developments and application directions of AIE-based antimicrobial materials are finally highlighted.

In Situ Hypoxia-Induced Supramolecular Perylene Diimide Radical Anions in Tumors for Photothermal Therapy with Improved Specificity.

Considering that hypoxia is closely associated with tumor proliferation, invasion, metastasis, and drug resistance, it is of great significance to overcome hypoxia in tumor treatment. Herein, we report a hypoxia-induced specific photothermal therapy (PTT) based on the photothermal agent of supramolecular perylene diimide radical anions. Hypoxic regions in various tumors display strong reductive ability, and in such environments the supramolecular complex of a perylene diimide derivative and cucurbit[7]uril could be reduced to supramolecular perylene diimide radical anions. Benefiting from the strong NIR absorption and good photothermal conversion performance of the in situ generated supramolecular perylene diimide radical anions, the hypoxia-induced PTT strategy exhibits excellent photothermal therapeutic efficiency as well as good specificity and biological safety. Moreover, hypoxia inducible factor expression of tumors decreases to the normal level after PTT treatment. It is anticipated that such a hypoxia-induced specific PTT strategy opens new horizons for photothermal therapy against hypoxic tumors with improved specificity and safety.

Supramolecular cancer photoimmunotherapy based on precise peptide self-assembly design.

Combinational photoimmunotherapy (PIT) is considered to be an ideal strategy for the treatment of highly recurrent and metastatic cancer, because it can ablate the primary tumor and provide in situ an autologous tumor vaccine to induce the host immune response, ultimately achieving the goal of controlling tumor growth and distal metastasis. Significant efforts have been devoted to enhancing the immune response caused by phototherapy-eliminated tumors. Recently, supramolecular PIT nanoagents based on precise peptide self-assembly design have been employed to improve the efficacy of photoimmunotherapy by utilizing the stability, targeting capability and flexibility of drugs, increasing tumor immunogenicity and realizing the synergistic amplification of immune effects through multiple pathways and collaborative strategy. This review summarizes peptide-based supramolecular PIT nanoagents for phototherapy-synergized cancer immunotherapy and its progress in enhancing the effect of photoimmunotherapy, especially focusing on the design of peptide-based PIT nanoagents, the progress of bioactive peptides combined photoimmunotherapy, and the synergistic immune-response mechanism.

Characterization and diabetic wound healing benefits of protein-polysaccharide complexes isolated from an animal ethno-medicine Periplaneta americana L.

Periplaneta americana L. (PA), a type of animal medicine, has been widely used for wound healing in clinical settings. In order to further investigate the bioactive wound healing substances in PA, crude PA protein-polysaccharide complexes were further purified by cellulose DE-52 and Sephadex G100 chromatography in succession. Among these isolated fractions, two fractions eluted by 0.3 M and 0.5 M NaCl with the higher yield, respectively named PaPPc2 and PaPPc3 respectively, were chosen for the wound healing experiments. Mediated by HPGPC, amino acid and monosaccharide composition analysis, circular dichroism spectrum, glycosylation type, FT-IR, and 1H NMR analysis, the characterization of PaPPc2 and PaPPc3 was implemented. And then, the benefits of PaPPcs to promote cell proliferation, migration, and tube formation of HUVECs were determined in vitro, indicated these fractions would facilitate angiogenesis. Finally, as proof of concept, PaPPc2 and PaPPc3 were employed to accelerate the acute wounds of diabetic mice, involving in increase blood vessels and the amounts of angiogenesis-related cytokines (α-SMA, VEGF, and CD31). In short, this study provides an experimental basis to demonstrate the protein-polysaccharide complexes of Periplaneta americana L. as its wound healing bioactive substances.

Pectic polysaccharides from Biluochun Tea: A comparative study in macromolecular characteristics, fine structures and radical scavenging activities in vitro.

In this study, two acidic Biluochun Tea polysaccharides (BTP-A11 and BTP-A12) were investigated comparatively, which mainly consisted of Rha, Ara, Gal and GalA, possibly suggesting their pectic nature. Structurally, their galacturonan backbones composed of →4)-α-D-GalpA-(1→ and →2)-α-L-Rhap-(1→ were revealed similar, while Ara- and Gal-based branches attached to the O-2 of →2)-α-L-Rhap-(1→ were in distinctive types, proportions, extensibilities and branching degrees. This could lead to their different macromolecular characteristics, where BTP-A11 with higher Mw presented a more hyper-branched chain conformation and relatively higher structural flexibility/compactness, thereby resulting in a lower exclusion effect and an insufficient hydrodynamic volume. Besides, better radical scavenging activities in vitro were also determined for Gal-enriched BTP-A11, where a larger surface area containing more H-donating groups were related to its higher Mw, more hyper-branched conformation, lower DM and higher DA. Therefore, the understanding of structure-property-activity relationships was improved to some degrees for acidic Biluochun Tea polysaccharides, which could be potentially required for more applications in food, medical and cosmetic fields.

A 4arm-PEG macromolecule crosslinked chitosan hydrogels as antibacterial wound dressing.

In order to develop better wound dressings, a novel chitosan hydrogel (Cn-Nm gel) was designed and fabricated by using aldehyde-4-arm polyethylene glycol (4r-PEG-CHO) to crosslink the chitosan dissolved in alkaline solution, amino-4-arm polyethylene glycol (4r-PEG-NH2) was chosen as the additive simultaneously. The special dissolution technique and macromolecular crosslinking structure endows the Cn-Nm gels with better performance than that of gels prepared by acid dissolving method with micromolecule crosslinker. First, Cn-Nm gels own strong toughness with 500 kPa tensile strength and 1000% elongation, about 400% swelling ratio and fast water absorption rate. Second, about 300 kPa adhesive strength and strippability between the gels and skin is achieved. More importantly, Cn-Nm gels show nearly 100% antibacterial rate towards Escherichia coli and Staphylococcus aureus. Excellent biocompatibility is also proved by the mouse fibroblasts tests. All of the performance makes this developed chitosan-based gel be the potential candidate as a wound dressing.

Functional Macromolecular Adhesives for Bone Fracture Healing.

Compared with traditional internal fixation devices, bone adhesives are expected to exhibit remarkable advantages, such as improved fixation of comminuted fractures and maintained spatial location of fractured scattered bone pieces in treating bone injuries. In this review, different bone adhesives are summarized from the aspects of bone tissue engineering, and the applications of bone adhesives are emphasized. The concepts of "liquid scaffold" and "liquid plate" are proposed to summarize two different research directions of bone adhesives. Furthermore, significant advances of bone adhesives in recent years in mechanical strength, osseointegration, osteoconductivity, and osteoinductivity are discussed. We conclude this topic by providing perspectives on the state-of-the-art research progress and future development trends of bone adhesives. We hope this review will provide a comprehensive summary of bone adhesives and inspire more extensive and in-depth research on this subject.

The role of natural biological macromolecules: Deoxyribonucleic and ribonucleic acids in the formulation of new stable charge transfer complexes of thiophene Schiff bases for various life applications.

The ecofriendly cellulose and gelatin provided sustainable and abundant sugars: d-ribofuranose, and 2-Deoxy-ribofuranose (starting reactants for preparative synthetic green chemistry pathways of charge transfer complexes. The natural available sugars d-ribofuranose, and 2-Deoxy-ribofuranose were obtained from facile hydrolysis of cellulose and gelatin natural macromolecules. Successive, low cost and facile alkaline- and acid hydrolysis of Deoxyribonucleic acid (DNA, from gelatin animal source) and ribonucleic acid (RNA, from cellulose plant source) yield the simple sugars: d-ribofuranose and 2-Deoxy-ribofuranose. Eight optically and biologically active charge transfer complexes were prepared from the reaction of the above sugars efficiently intercalated with two new prepared thiophene Schiff Lewis (electron donors) bases: 2-((2Hydroxybenzylidene) amino)-4, 5, 6, 7-tetrahydrobenzo [b] thiophene-3-carbonitrile (D1, 2-((Furan-2ylmethylene) amino) 4,5,6,7 tetrahydrobenzo [b] thiophene-3-carbonitrile (D2). The chemical structures of these prepared Schiff bases were confirmed using the mass spectra. The successful intercalation of the sugar units with the Lewis bases was ascertained using powder x ray diffraction. The molecular structures of the reaction products were proposed based on FTIR, 1H NMR. The optical activity of charge transfer complexes were confirmed using UV-Vis. Absorption spectroscopy. The surface morphology, microstructures, and particle size of the donors and charge transfer complexes were determined using scanning electron microscopy (SEM). The Lewis bases (D1) and (D2) showed no antimicrobial activity, while their charge transfer complexes showed good antimicrobial activity, suggesting their pharmaceutical and medicinal applications due to the potent biological activity against wide spread microbial microorganisms of Gram positive and Gram positive bacteria as well as some fungal species.

Synthesis and Anticancer Activity of Triazole Linked Macrocycles and Heterocycles.

Synthesis of macrocylic enones starting from alkyl ether and triazole as a linker was achieved using click reaction and intramolecular aldol condensation. The newly synthesized macrocyclic enone was successfully utilized as a dipolarophile in 1,3-dipolar cycloaddition. The dipoles generated from hydrazine hydrochloride, hydroxylamine and guanidine hydrochloride were reacted with macrocyclic enone to give a new class of spiro aminopyrimidines, phenyl pyrazoles and isoxazoles grafted macrocycles in good yield. The structures of newly synthesized compounds were confirmed with IR, NMR and mass spectroscopy and evaluated for their anti cancer activity.

Supramolecular Coronation of Platinum(II) Complexes by Macrocycles: Structure, Relativistic DFT Calculations, and Biological Effects.

Platinum-based anticancer drugs are actively developed utilizing lipophilic ligands or drug carriers for the efficient penetration of biomembranes, reduction of side effects, and tumor targeting. We report the development of a supramolecular host-guest system built on cationic platinum(II) compounds bearing ligands anchored in the cavity of the macrocyclic host. The host-guest binding and hydrolysis process on the platinum core were investigated in detail by using NMR, MS, X-ray diffraction, and relativistic DFT calculations. The encapsulation process in cucurbit[7]uril unequivocally promotes the stability of hydrolyzed dicationic cis-[PtII(NH3)2(H2O)(NH2-R)]2+ compared to its trans isomer. Biological screening on the ovarian cancer lines A2780 and A2780/CP shows time-dependent toxicity. Notably, the reported complex and its ß-cyclodextrin (ß-CD) assembly achieve the same cellular uptake as cisplatin and cisplatin@ß-CD, respectively, while maintaining a significantly lower toxicity profile.

Nano Milk Protein-Mucilage Complexes: Characterization and Anticancer Effect.

The anticancer activity of natural compounds has recently attracted multidisciplinary research. In this study, the complexation of milk proteins (MP) with Isabgol husk mucilage (IHM) and Ziziphus spina-christi mucilage (NabM) was investigated. In this context, the physicochemical properties of milk protein mucilage complexes (MPMC) including pH, Carr's index, water solubility, and water absorption indices were measured, and the flow behavior was studied. In addition, the amino acid profile, protein digestibility, and phenolic and flavonoids content of MPMC were explored, and the microstructure of the complexes was visualized using transmission electron microscopy. The antioxidant and anticancer potencies of MPMC against two cancerous cell lines, human liver cancer HEPG-2 and breast cancer MCF-7, in comparison with two normal cell lines, namely, Bj-1 and MCF-12F, were tested using neutral red uptake assay. The results revealed that MPMC had scavenging activity against DPPH, ABTS, and HS radicals. Moreover, MPMC has the potential to prevent DNA damage induced by oxidative stress in Type-Fenton's reaction. The results of the neutral red assay showed significant growth inhibition of both HEPG-2, MCF-7, whereas no significant cytotoxic effect was detected against Bj-1 and MCF-12F. RT-qPCR results indicated MPMC stimulated apoptosis as revealed by the upregulation of the pro-apoptosis gene markers Casepase-3, p53, Bax. Meanwhile, the anti-apoptosis Bcl-2 gene was downregulated. However, no significant difference was observed in normal cell lines treated with MPMC. In conclusion, MPMC can be considered as a promising anticancer entity that can be used in the development of novel cancer therapeutics with comparable activity and minimal side effects compared to conventional cancer chemotherapies.

Pillar[6]arene-Based Supramolecular Nanocatalysts for Synergistically Enhanced Chemodynamic Therapy by the Intracellular Cascade Reaction.

Chemodynamic therapy (CDT) based on the intracellular Fenton reaction has become increasingly explored in cancer treatment. However, the mildly acidic tumor microenvironment and the limited amount of intracellular hydrogen peroxide (H2O2) will create issues for CDT to perform a sustained and high-efficiency treatment. Therefore, how to selectively reduce the pH value and augment the amount of H2O2 in tumor tissues has become the key factor for realizing excellent CDT. Besides, the majority of the reported CDT systems have been constructed from iron-based inorganic or metal-organic framework nanomaterials due to the decisive role of metals in CDT, which restricts the development of CDT. In this study, inspired by the host-guest interactions between pillar[6]arene and ferrocene, a ternary pillar[6]arene-based supramolecular nanocatalyst (GOx@T-NPs) for CDT is reported for the first time. GOx@T-NPs not only exhibited a high-efficiency catalytic ability to convert glucose into hydroxyl radicals (•OH) and to reduce the pH value inside cancer cells for significant enhancement of the CDT effect, but they also showed sensitive glutathione-induced camptothecin (CPT) prodrug release capacity for further improving the efficiency of CDT. Hence, GOx@NPs possessed excellent ability to synergistically enhance the CDT. Additionally, an antitumor mechanism study showed that the prominent tumor inhibition capacity of GOx@T-NPs was derived from trimodal synergistic interactions of CDT, starvation therapy, and chemotherapy. Moreover, GOx@T-NPs manifested good biocompatibility and tumor selectivity with few side effects in major organs. This work broadens the range of materials available for CDT and demonstrates new developments in pillar[n]arene-based multimodal synergistic treatment systems.

Detoxification of the Toxic Sulfur Mustard Simulant by a Supramolecular Antidote in Vitro and in Vivo.

Although great potential hazards and threats still occur from sulfur mustard, there are no specific medicine or therapy for the intoxication of sulfur mustard. Herein, we have demonstrated a supramolecular approach for the detoxification of the sulfur mustard simulant CEES (4) in vitro and in vivo by carboxylatopillar[5]arene potassium salts (CP[5]AK 1) efficiently based on host-guest interactions. The encapsulation of CEES (4) by the cavity of the pillar[5]arene 2 is driven by C-H···π interactions between CEES (4) and the electron-rich cavity of pillar[5]arene 2, which was investigated by 1H NMR titration, density functional theory studies, and the independent gradient model studies. CEES (4) is degradated to the reactive sulfonium salts quickly in aqueous media, resulting in the alkylation of DNA and proteins. The sulfonium salts can be encapsulated by CP[5]AK 1 efficiently, which accelerates the degradation of the sulfonium salts about 14 times. The cell and animal experiments indicated that the bioactivities of the sulfonium salts are inhibited with the formation of stable host-guest complexes, and CP[5]AK 1 has a good therapeutic effect on the damages caused by CEES (4) at either pre- or post-treatments. Due to the low cytotoxicity and good therapeutic effect, the anionic pillar[5]arenes are expected to be developed as specific antidotes against sulfur mustard (HD).

Supramolecular Drug Delivery System from Macrocycle-Based Self-Assembled Amphiphiles for Effective Tumor Therapy.

Intelligent drug delivery systems (DDSs) that can improve therapeutic outcomes of antitumor agents and decrease their side effects are urgently needed to satisfy special requirements of treatment of malignant tumors in clinics. Here, the fabrication of supramolecular self-assembled amphiphiles based on the host-guest recognition between a cationic water-soluble pillar[6]arene (WP6A) host and a sodium decanesulfonate guest (G) is reported. The chemotherapeutic agent doxorubicin hydrochloride (DOX) can be encapsulated into the formed vesicle (G/WP6A) to construct supramolecular DDS (DOX@G/WP6A). WP6A affords strong affinities to G to avoid undesirable off-target leakage during delivery. Nanoscaled DOX@G/WP6A is capable of preferentially accumulating in tumor tissue via enhanced permeability and retention (EPR) effect. After internalization by tumor cells, the abundant adenosine triphosphate (ATP) binds competitively with WP6A to trigger the disintegration of self-assembled vesicles with the ensuing release of DOX. In vitro and in vivo research confirmed that DOX@G/WP6A is not only able to promote antitumor efficacy but also reduce DOX-related systemic toxicity. The above favorable findings are ascribed to the formation of ternary self-assembly, which profits from the combination of the factors of the EPR effect and the ATP-triggered release.