A Pillar[5]arene-Containing Metal-Organic Framework for Rapid and Highly Capable Adsorption of a Mustard Gas Simulant.

Mustard gas causes irreversible damage upon inhalation or contact with the human body. Consequently, the development of adsorbents for effective interception of mustard gas at low concentrations and high flow rates is an urgent necessity. Here we report a stable porous pillar[5]arene-containing metal-organic framework (MOF) based on zirconium (EtP5-Zr-scu), demonstrating that embedding pillar[5]arene units in MOFs can provide specific binding sites for efficient adsorption of a mustard gas simulant, 2-chloroethyl ethyl sulfide (CEES). EtP5-Zr-scu achieves a higher capacity and more rapid adsorption compared to its counterpart without embedded pillar[5]arene units (H4tcpt-Zr-scu) and perethylated pillar[5]arene (EtP5) alone. Single crystal X-ray diffraction and solid-state nuclear magnetic resonance reveal that the enhanced performance of EtP5-Zr-scu is derived from the host-guest complexation between CEES and pillar[5]arene moieties. Moreover, breakthrough experiments confirmed that the interception performance of EtP5-Zr-scu against CEES (800 ppm, 120 mL/min) was significantly improved (566 min/g) compared with H4tcpt-Zr-scu (353 min/g) and EtP5 (0.873 min/g), attributed to the integration of open channels with specific recognition sites. This work marks a significant advancement in the development of macrocycle-incorporated crystalline framework materials with recognition sites for the efficient capture of guest molecules.

A Cascade-Amplified Pyroptosis Inducer: Optimizing Oxidative Stress Microenvironment by Self-Supplying Reactive Nitrogen Species Enables Potent Cancer Immunotherapy.

Selective generation of sufficient pyroptosis inducers at the tumor site without external stimulation holds immense significance for a longer duration of immunotherapy. Here, we report a cascade-amplified pyroptosis inducer CSCCPT/SNAP that utilizes reactive nitrogen species (RNS), self-supplied from the diffusion-controlled reaction between reactive oxygen species (ROS) and nitric oxide (NO) to potentiate pyroptosis and immunotherapy, while both endogenous mitochondrial ROS stimulated by released camptothecin and released NO initiate pyroptosis. Mechanistically, cascade amplification of the antitumor immune response is prompted by the cooperation of ROS and NO and enhanced by RNS with a long lifetime, which could be used as a pyroptosis trigger to effectively compensate for the inherent drawbacks of ROS, resulting in long-lasting pyroptosis for favoring immunotherapy. Tumor growth is efficiently inhibited in mouse melanoma tumors through the facilitation of reactive oxygen/nitrogen species (RONS)-NO synergy. In summary, our therapeutic approach utilizes supramolecular engineering and nanotechnology to integrate ROS producers and NO donors of tumor-specific stimulus responses into a system that guarantees synchronous generation of these two reactive species to elicit pyroptosis-evoked immune response, while using self-supplied RNS as a pyroptosis amplifier. RONS-NO synergy achieves enhanced and sustained pyroptosis and antitumor immune responses for robust cancer immunotherapy.

Supramolecular Coordination Complexes for Synergistic Cancer Therapy.

Supramolecular coordination complexes (SCCs) are predictable and size-tunable supramolecular self-assemblies constructed through directional coordination bonds between readily available organic ligands and metallic receptors. Based on planar and 3D structures, SCCs can be mainly divided into two categories: metallacycles (e.g., rhomboidal, triangular, rectangular, and hexagonal) and metallacages (e.g., tetrahedral, hexahedral, and dodecahedral). The directional coordination bonds enable the efficient formation of metallacycles and metallacages with well-defined architectures and geometries. SCCs exhibit several advantages, including good directionality, strong interaction force, tunable modularity, and good solution processability, making them highly attractive for biomedical applications, especially in cellular imaging and cancer therapy. Compared with their molecular precursors, SCCs demonstrate enhanced cellular uptake and a strengthened tumor accumulation effect, owing to their inherently charged structures. These properties and the chemotherapeutic potential inherent to organic platinum complexes have promoted their widespread application in antitumor therapy. Furthermore, the defined structures of SCCs, achieved via the design modification of assembly elements and introduction of different functional groups, enable them to combat malignant tumors through multipronged treatment modalities. Because the development of cancer-treatment methodologies integrated in clinics has evolved from single-modality chemotherapy to synergistic multimodal therapy, the development of functional SCCs for synergistic cancer therapy is crucial. While some pioneering reviews have explored the bioapplications of SCCs, often categorized by a specific function or focusing on the specific metal or ligand types, a comprehensive exploration of their synergistic multifunctionality is a critical gap in the current literature.In this Account, we focus on platinum-based SCCs and their applications in cancer therapy. While other metals, such as Pd-, Rh-, Ru-, and Ir-based SCCs, have been explored for cancer therapy by Therrien and Casini et al., platinum-based SCCs have garnered significant interest, owing to their unique advantages in antitumor therapy. These platinum-based SCCs, which enhance antitumor efficacy, are considered prominent candidates for cancer therapies owing to their desirable properties, such as potent antitumor activity, exceptionally low systemic toxicity, active tumor-targeting ability, and enhanced cellular uptake. Furthermore, diverse diagnostic and therapeutic modalities (e.g., chemotherapy, photothermal therapy, and photodynamic therapy) can be integrated into a single platform based on platinum-based SCCs for cancer therapy. Consequently, herein, we summarize our recent research on platinum-based SCCs for synergistic cancer therapy with particular emphasis on the cooperative interplay between different therapeutic methods. In the Conclusions section, we present the key advancements achieved on the basis of our research findings and propose future directions that may significantly impact the field.

Dual-Responsive Supramolecular Polymeric Nanomedicine for Self-Cascade Amplified Cancer Immunotherapy.

Insufficient tumor immunogenicity and immune escape from tumors remain common problems in all tumor immunotherapies. Recent studies have shown that pyroptosis, a form of programmed cell death that is accompanied by immune checkpoint inhibitors, can induce effective immunogenic cell death and long-term immune activation. Therapeutic strategies to jointly induce pyroptosis and reverse immunosuppressive tumor microenvironments are promising for cancer immunotherapy. In this regard, a dual-responsive supramolecular polymeric nanomedicine (NCSNPs) to self-cascade amplify the benefits of cancer immunotherapy is designed. The NCSNPs are formulated by ß-cyclodextrin coupling nitric oxide (NO) donor, a pyroptosis activator, and NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor, and self-assembled through host-guest molecular recognition and hydrophobic interaction to obtain nanoparticles. NCSNPs possess excellent tumor accumulation and bioavailability attributed to ingenious supramolecular engineering. The study not only confirms the occurrence of NO-triggered pyroptosis in tumors for the first time but also reverses the immunosuppressive microenvironment in tumor sites via an IDO inhibitor by enhancing the infiltration of cytotoxic T lymphocytes, to achieve remarkable inhibition of tumor proliferation. Thus, this study provides a novel strategy for cancer immunotherapy.

Biodegradable Lipid-Modified Poly(Guanidine Thioctic Acid)s: A Fortifier of Lipid Nanoparticles to Promote the Efficacy and Safety of mRNA Cancer Vaccines.

Lipid nanoparticles (LNPs)-based messenger RNA (mRNA) therapeutics have emerged with promising potentials in the fields of infectious diseases, cancer vaccines, and protein replacement therapies; however, their therapeutic efficacy and safety can still be promoted by the optimization of LNPs formulations. Unfortunately, current LNPs suffer from increased production of reactive oxygen species during translation, which leads to a decreased translation efficiency and the onset of inflammation and other side effects. Herein, we synthesize a lipid-modified poly(guanidine thioctic acid) polymer to fabricate novel LNPs for mRNA vaccines. The acquired G-LNPs significantly promote the translation efficiency of loaded mRNA and attenuate inflammation after vaccination through the elimination of reactive oxygen species that are responsible for translational inhibition and inflammatory responses. In vivo studies demonstrate the excellent antitumor efficacy of the G-LNPs@mRNA vaccine, and two-dose vaccination dramatically increases the population and infiltration of cytotoxic T cells due to the intense antitumor immune responses, thus generating superior antitumor outcomes compared with the mRNA vaccine prepared from traditional LNPs. By synergy with immune checkpoint blockade, the tumor inhibition of G-LNPs@mRNA is further boosted, indicating that G-LNPs-based mRNA vaccines will be powerful and versatile platforms to combat cancer.

Drug-initiated poly(thiocitc acid) polymer incorporating host-guest interaction for cancer combination chemotherapy.

Combination chemotherapy has shown considerable promise for cancer therapy. However, the hydrophobicity of chemotherapeutic agents and the difficulties of precise drug co-administration severely hinder the development of combination chemotherapy. Herein, we develop a polymeric drug delivery system (D-PTA-CD) to provide robust loading capacity, glutathione-responsive drug release, and precise combination therapy. The vehicle is prepared based on poly(thioctic acid) (PTA) polymers using DM1, a chemotherapeutic agent, as the initiator to endow the vehicle with cancer-inhibiting activity. ß-cyclodextrins are incorporated into the side chains to enhance drug loading capacity via host-guest interactions. Attributing to the sufficient disulfide bond on the backbone, D-PTA-CD exhibits accelerated drug release triggered by elevated glutathione levels. Doxorubicin (DOX) and camptothecin (CPT) are encapsulated by D-PTA-CD to afford the combination chemotherapy nanoparticles (NP), DOX-NP, and CPT-NP, respectively, which exhibit significant synergetic anti-cancer effects, highlighting the enormous potential of D-PTA-CD as a versatile drug delivery platform for cancer combination chemotherapy.

Supramolecular Genome Editing: Targeted Delivery and Endogenous Activation of CRISPR/Cas9 by Dynamic Host-Guest Recognition.

We synthesize supramolecular poly(disulfide) (CPS) containing covalently attached cucurbit[7]uril (CB[7]), which is exploited not only as a carrier to deliver plasmid DNA encoding destabilized Cas9 (dsCas9), but also as a host to include trimethoprim (TMP) by CB[7] moieties through the supramolecular complexation to form TMP@CPS/dsCas9. Once the plasmid is transfected into tumor cells by CPS, the presence of polyamines can competitively trigger the decomplexation of TMP@CPS, thereby displacing and releasing TMP from CB[7] to stabilize dsCas9 that can target and edit the genomic locus of PLK1 to inhibit the growth of tumor cells. Following the systemic administration of TMP@CPS/dsCas9 decorated with hyaluronic acid (HA), tumor-specific editing of PLK1 is detected due to the elevated polyamines in tumor microenvironment, greatly minimizing off-target editing in healthy tissues and non-targeted organs. As the metabolism of polyamines is dysregulated in a wide range of disorders, this study offers a supramolecular approach to precisely control CRISPR/Cas9 functions under particular pathological contexts.

Recent Progress of Supramolecular Chemotherapy Based on Host-Guest Interactions.

Chemotherapy is widely recognized as an effective approach for treating cancer due to its ability to eliminate cancer cells using chemotherapeutic drugs. However, traditional chemotherapy suffers from various drawbacks, including limited solubility and stability of drugs, severe side effects, low bioavailability, drug resistance, and challenges in tracking treatment efficacy. These limitations greatly hinder its widespread clinical application. In contrast, supramolecular chemotherapy, which relies on host-guest interactions, presents a promising alternative by offering highly efficient and minimally toxic anticancer drug delivery. In this review, an overview of recent advancements in supramolecular chemotherapy based on host-guest interactions is provided. The significant role it plays in guiding cancer therapy is emphasized. Drawing on a wealth of cutting-edge research, herein, a timely and valuable resource for individuals interested in the field of supramolecular chemotherapy or cancer therapy, is presented. Furthermore, this review contributes to the progression of the field of supramolecular chemotherapy toward clinical application.

Recent Development of Supramolecular Cancer Theranostics Based on Cyclodextrins: A Review.

With the development of personalized medical demands for precise diagnosis, rational management and effective cancer treatment, supramolecular theranostic systems have received widespread attention due to their reversibly switchable structures, sensitive response to biological stimuli and integration ability for multiple capabilities in a single platform with a programmable fashion. Cyclodextrins (CDs), benefiting from their excellent characteristics, such as non-toxicity, easy modification, unique host-guest properties, good biocompatibility, etc., as building blocks, serve as an all-purpose strategy for the fabrication of a supramolecular cancer theranostics nanodevice that is capable of biosafety, controllability, functionality and programmability. This review focuses on the supramolecular systems of CD-bioimaging probes, CD-drugs, CD-genes, CD-proteins, CD-photosensitizers and CD-photothermal agents as well as multicomponent cooperation systems with regards to building a nanodevice with functions of diagnosis and (or) therapeutics of cancer treatment. By introducing several state-of-the-art examples, emphasis will be placed on the design of various functional modules, the supramolecular interaction strategies under the fantastic topological structures and the hidden "bridge" between their structures and therapeutic efficacy, aiming for further comprehension of the important role of a cyclodextrin-based nanoplatform in advancing supramolecular cancer theranostics.

Guanidine-modified nanoparticles as robust BTZ delivery carriers and activators of immune responses.

Dendritic cells (DCs), the primary antigen-presenting cells in the immune system, play a critical role in regulating tumor immune responses. However, the tumor immunosuppressive microenvironment severely impedes the process of antigen-presenting and DC maturation, thereby limiting the efficacy of cancer immunotherapy. In this work, a pH-responsive polymer nanocarrier (PAG) modified with aminoguanidine (AG) was constructed for the efficient delivery of bortezomib (BTZ) through bidentate hydrogen bonds and electrostatic adsorption formed between guanidine groups of PAG and boronic acid groups of BTZ. The obtained PAG/BTZ nanoparticles exhibited pH-responsive release of BTZ and AG in the acidic tumor microenvironment. On the one hand, BTZ induced potent immune activation by eliciting immunogenic cell death (ICD) and releasing damage-associated molecular patterns. On the other hand, the cationic AG significantly promoted antigen uptake by DCs and activated DC maturation. As a result, PAG/BTZ significantly stimulated tumoral infiltration of cytotoxic T lymphocytes (CTLs) and triggered robust antitumor immune responses. Thus, it showed potent antitumor efficacy when synergizing with an immune checkpoint-blocking antibody.

Polymerization in living organisms.

Vital biomacromolecules, such as RNA, DNA, polysaccharides and proteins, are synthesized inside cells via the polymerization of small biomolecules to support and multiply life. The study of polymerization reactions in living organisms is an emerging field in which the high diversity and efficiency of chemistry as well as the flexibility and ingeniousness of physiological environment are incisively and vividly embodied. Efforts have been made to design and develop in situ intra/extracellular polymerization reactions. Many important research areas, including cell surface engineering, biocompatible polymerization, cell behavior regulation, living cell imaging, targeted bacteriostasis and precise tumor therapy, have witnessed the elegant demeanour of polymerization reactions in living organisms. In this review, recent advances in polymerization in living organisms are summarized and presented according to different polymerization methods. The inspiration from biomacromolecule synthesis in nature highlights the feasibility and uniqueness of triggering living polymerization for cell-based biological applications. A series of examples of polymerization reactions in living organisms are discussed, along with their designs, mechanisms of action, and corresponding applications. The current challenges and prospects in this lifeful field are also proposed.

Supramolecular engineering of cell membrane vesicles for cancer immunotherapy.

The clinical translation of nanomedicines has been strongly hampered by the limitations of delivery vehicles, promoting scientists to search for novel nanocarriers. Although cell membrane-based delivery systems have attracted extensive attention, further functionalizations are urgently desired to augment their theranostic functions. We propose a cell-friendly supramolecular strategy to engineer cell membranes utilizing cyclodextrin-based host-guest molecular recognitions to fix the defects arising from chemical and genetic modifications. In this study, the supramolecular cell membrane vesicles (SCMVs) specifically accumulate in tumors, benefiting from tumor-homing capability and the enhanced permeability and retention effect. SCMVs co-delivering indocyanine green and an indoleamine 2,3-dioxygenase inhibitor effectively ablate tumors combining photodynamic therapy and immunotherapy. Driven by host-guest inclusion complexation, SCMVs successfully encapsulate resiquimod to repolarize tumor-associated macrophages into M1 phenotype, synergizing with immune checkpoint blockade therapy. This supramolecular engineering methodology based on noncovalent interactions presents a generalizable and cell-friendly tactic to develop living cell-originated nanomaterials for precise cancer therapy.

Suprasomes Based on Host-Guest Molecular Recognition: An Excellent Alternative to Liposomes in Cancer Theranostics.

Liposomes and polymersomes, typical vesicular drug delivery systems (DDSs), have faced some limitations in cancer theranostics. Suprasomes, supramolecular vesicles assembled from amphiphiles linked by noncovalent interactions, show potential as new generation of vesicular DDSs. We construct suprasomes based on host-guest recognition, by which the desired functions can be integrated into carriers without tedious synthesis. Photothermally active host-guest complex is formed between a functional guest and pillar[5]arene, which further self-assembles into hollow suprasomes. A supramolecular nanomedicine is developed by encapsulating cisplatin in the suprasomes. The obtained cisplatin@Suprasomes achieve excellent anticancer efficacy and anti-metastasis combining chemotherapy and photothermal therapy, which ablate the tumors without relapse and metastasis. This work demonstrates the facile functionalization of suprasomes, holding promise as alternatives to liposomes and polymersomes.

Controlling Intracellular Enzymatic Self-Assembly of Peptide by Host-Guest Complexation for Programming Cancer Cell Death.

Controlling the enzymatic reaction of macromolecules in living systems plays an essential role in determining the biological functions, which remains challenging in the synthetic system. This work shows that host-guest complexation could be an efficient strategy to tune the enzymatic self-assembly of the peptide. The formed host-guest complexation prevents the enzymatic kinetics of peptide assemblies on the cell surface and promotes cellular uptake of assemblies. For uptake inside cells, the host-guest complex undergoes dissociation in the acidic lysosome, and the released peptide further self-assembles inside the mitochondria. Accumulating assemblies at mitochondria induce the ferroptosis of cancer cells, resulting in cancer cell death in vitro and the tumor-bearing mice model. As the first example of using host-guest complexation to modulate the kinetics of enzymatic self-assembly, this work provides a general method to control enzymatic self-assembly in living cells for selective programming cancer cell death.

A Hybrid Supramolecular Polymeric Nanomedicine for Cascade-Amplified Synergetic Cancer Therapy.

Supramolecular nanomedicines have shown great merits in cancer therapy, but their clinical translation is hampered by monotonous therapeutic modality and unsatisfactory antitumor performance. Herein, a hybrid supramolecular polymeric nanomedicine (SNPs) is developed based on ß-cyclodextrin/camptothecin (CPT) host-guest molecular recognition and iron-carboxylate coordination. Iron ions stabilizing SNPs catalyze the conversion of intracellular hydrogen peroxide into highly toxic hydroxyl radical through a Fenton reaction, which further cleaves the thioketal linker of the supramolecular monomer to release potent CPT, thus amplifying the therapeutic efficacy by combining chemodynamic therapy and chemotherapy. The combination therapy stimulates antitumor immunity and promotes intratumoral infiltration of cytotoxic T lymphocytes by triggering immunogenic cell death. In synergy with PD-L1 checkpoint blockade, SNPs enables enhanced immune therapy and a long-term tumor remission.

NIR-II phototherapy agents with aggregation-induced emission characteristics for tumor imaging and therapy.

As one of the major public health concerns, malignant tumors threaten people's lives. With the increasing demand for early accurate diagnosis and the safe treatment of tumors, non-invasive optical imaging (including fluorescence imaging and photoacoustic imaging) and phototherapy (including photothermal therapy and photodynamic therapy) have received much attention. In particular, light in the near-infrared second region (NIR-II) has been attracting research interest, owing to its deep penetration, minimal tissue autofluorescence, and decreased tissue absorption and scattering. Among all biological materials, organic nanomaterials with aggregation-induced emission (AIE) properties have attracted significant attention, owing to various incomparable advantages, such as high brightness, good photostability, tunable photophysical properties, and good biosafety. To modulate the working optical region of AIE molecules to the NIR-II region, many researchers have tried a variety of methods in recent years, and the focus of this review is to summarize the three most common methods from the perspective of molecular design strategies. In addition, this article briefly reviews the recent five-year progress of NIR-II AIE luminophores in tumor imaging and phototherapy applications. The research status is also summarized and prospected, with the hope of contributing to further research.

An NIR Discrete Metallacycle Constructed from Perylene Bisimide and Tetraphenylethylene Fluorophores for Imaging-Guided Cancer Radio-Chemotherapy.

To promote the clinical theranostic performances of platinum-based anticancer drugs, imaging capability is urgently desired, and their chemotherapeutic efficacy needs to be upgraded. Herein, a theranostic metallacycle (M) is developed for imaging-guided cancer radio-chemotherapy using perylene bisimide fluorophore (PPy) and tetraphenylethylene-based di-Pt(II) organometallic precursor (TPE-Pt) as building blocks. The formation of this discrete supramolecular coordination complex facilitates the encapsulation of M by a glutathione (GSH)-responsive amphiphilic block copolymer to prepare M-loaded nanoparticles (MNPs). TPE-Pt acts as a chemotherapeutic drug and also an excellent radiosensitizer, thus incorporating radiotherapy into the nanomedicine to accelerate the therapeutic efficacy and overcome drug resistance. The NIR-emission of PPy is employed to detect the intracellular delivery and tissue distribution of MNPs in real time. In vitro and in vivo investigations demonstrate the excellent anticancer efficacy combining chemotherapy and radiotherapy; the administration of this nanomedicine effectively inhibits the tumor growth and greatly extends the survival rate of cisplatin-resistant A2780CIS-tumor-bearing mice. Guided by in vivo fluorescence imaging, radio-chemotherapy is precisely carried out, which facilitates boosting of the therapeutic outcomes and minimizing undesired side effects. The success of this theranostic system brings new hope to supramolecular nanomedicines for their potential clinical translations.

Chemoresponsive Supramolecular Polypseudorotaxanes with Infinite Switching Capability.

Chemoresponsive supramolecular systems with infinite switching capability are important for applications in recycled materials and intelligent devices. To attain this objective, here a chemoresponsive polypseudorotaxane is reported on the basis of a bis(p-phenylene)-34-crown-10 macrocycle (H) and a cyano-substituted viologen guest (G). H and G form a [2]pseudorotaxane (H⊃G) both in solution and in the solid state. Upon addition of AgSF6 , a polypseudorotaxane (denoted as [H⋅G⋅Ag]n ) forms as synergistically driven by host-guest complexation and metal-coordination interactions. [H⋅G⋅Ag]n depolymerizes into a [3]pseudorotaxane (denoted as H2 ⋅G⋅Ag2 ⋅acetone2 ) upon addition of H and AgSF6 , while it reforms with successive addition of G. The transformations between [H⋅G⋅Ag]n and H2 ⋅G⋅Ag2 ⋅acetone2 can be switched for infinite cycles, superior to the conventional chemoresponsive supramolecular polymeric systems with limited switching capability.

Selective adsorptive separation of cyclohexane over benzene using thienothiophene cages.

The selective separation of benzene (Bz) and cyclohexane (Cy) is one of the most challenging chemical separations in the petrochemical and oil industries. In this work, we report an environmentally friendly and energy saving approach to separate Cy over Bz using thienothiophene cages (ThT-cages) with adaptive porosity. Interestingly, cyclohexane was readily captured selectively from an equimolar benzene/cyclohexane mixture with a purity of 94%. This high selectivity arises from the C-H⋯S, C-H⋯π and C-H⋯N interactions between Cy and the thienothiophene ligand. Reversible transformation between the nonporous guest-free structure and the host-guest assembly, endows this system with excellent recyclability with minimal energy requirements.

Supramolecular cancer nanotheranostics.

Among the many challenges in medicine, the treatment and cure of cancer remains an outstanding goal given the complexity and diversity of the disease. Nanotheranostics, the integration of therapy and diagnosis in nanoformulations, is the next generation of personalized medicine to meet the challenges in precise cancer diagnosis, rational management and effective therapy, aiming to significantly increase the survival rate and improve the life quality of cancer patients. Different from most conventional platforms with unsatisfactory theranostic capabilities, supramolecular cancer nanotheranostics have unparalleled advantages in early-stage diagnosis and personal therapy, showing promising potential in clinical translations and applications. In this review, we summarize the progress of supramolecular cancer nanotheranostics and provide guidance for designing new targeted supramolecular theranostic agents. Based on extensive state-of-the-art research, our review will provide the existing and new researchers a foundation from which to advance supramolecular cancer nanotheranostics and promote translationally clinical applications.