A Dicyanomethyl Radical Conjugated with a Pyridylamino Group: Combining Radical-based Dynamic Covalent Chemistry and Coordination Chemistry

In this work, we aimed to develop a dicyanomethyl radical that undergoes both reversible C−C bond formation/dissociation and metal-ligand coordination reactions to combine dynamic covalent chemistry (DCC) based on organic radicals with coordination chemistry. We have previously reported a dicyanomethyl radical conjugated with a triphenylamine ( 1 ⋅) that exhibits a monomer/dimer equilibrium between the σ-bonded dimer ( 1₂ ). We designed and synthesized a novel dicyanomethyl radical with a pyridyl group as a coordination point ( 2 ⋅) by replacing the phenyl group of 1 ⋅ with a 3-pyridyl group. We showed that 2 ⋅ is also in an equilibrium with the σ-bonded dimer ( 2₂ ) in solution and has suitable thermodynamic parameters for application in DCC. 2₂ coordinates to PdCl₂ in a 2 : 2 ratio to selectively form a metallamacrocycle ( 2₂ )₂(PdCl₂)₂, and its structure was clarified by single crystal X-ray analysis. Variable-temperature NMR, ESR, and electronic absorption measurements revealed that ( 2₂ )₂(PdCl₂)₂ also undergoes the reversible C−C bond formation/dissociation reaction. Ligand-exchange experiment showed that 2₂ was liberated from ( 2₂ )₂(PdCl₂)₂ by the addition of another ligand with a higher affinity for Pd^II. This work demonstrated that DCC based on dicyanomethyl radicals works orthogonally to metal-ligand coordination reactions.     

Tandem Guest-Host-Receptor Recognitions Precisely Guide Ciprofloxacin to Eliminate Intracellular Staphylococcus aureus

Staphylococcus aureus (S. aureus) is able to hide within host cells to escape immune clearance and antibiotic action, causing life-threatening infections. To boost the therapeutic efficacy of antibiotics, new intracellular delivery approaches are urgently needed. Herein, by rational design of an adamantane (Ada)-containing antibiotic-peptide precursor Ada-Gly-Tyr-Val-Ala-Asp-Cys(StBu)-Lys(Ciprofloxacin)-CBT ( Cip-CBT-Ada ), we propose a strategy of tandem guest-host-receptor recognitions to precisely guide ciprofloxacin to eliminate intracellular S. aureus. Via guest-host recognition, Cip-CBT-Ada is decorated with a β-cyclodextrin-heptamannoside ( CD-M ) derivative to yield Cip-CBT-Ada/CD-M , which is able to target mannose receptor-overexpressing macrophages via multivalent ligand-receptor recognition. After uptake, Cip-CBT-Ada/CD-M undergoes caspase-1 (an overexpressed enzyme during S. aureus infection)-initiated CBT-Cys click reaction to self-assemble into ciprofloxacin nanoparticle Nano-Cip . In vitro and in vivo experiments demonstrate that, compared with ciprofloxacin or Cip-CBT-Ada , Cip-CBT-Ada/CD-M shows superior intracellular bacteria elimination and inflammation alleviation efficiency in S. aureus-infected RAW264.7 cells and mouse infection models, respectively. This work provides a supramolecular platform of tandem guest-host-receptor recognitions to precisely guide antibiotics to eliminate intracellular S. aureus infection efficiently.     

Nano Proteolysis Targeting Chimeras (PROTACs) with Anti-Hook Effect for Tumor Therapy

Proteolysis targeting chimera (PROTAC) is an emerging pharmacological modality with innovated post-translational protein degradation capabilities. However, off-target induced unintended tissue effects and intrinsic “hook effect” hinder PROTAC biotechnology to be maturely developed. Herein, an intracellular fabricated nano proteolysis targeting chimeras (Nano-PROTACs) modality with a center-spoke degradation network for achieving efficient dose-dependent protein degradation in tumor is reported. The PROTAC precursors are triggered by higher GSH concentrations inside tumor cells, which subsequently in situ self-assemble into Nano-PROTACs through intermolecular hydrogen bond interactions. The fibrous Nano-PROTACs can form effective polynary complexes and E3 ligases degradation network with multi-binding sites, achieving dose-dependent protein degradation with “anti-hook effect”. The generality and efficacy of Nano-PROTACs are validated by degrading variable protein of interest (POI) such as epidermal growth factor receptor (EGFR) and androgen receptor (AR) in a wide-range dose-dependent manner with a 95 % degradation rate and long-lasting potency up to 72 h in vitro. Significantly, Nano-PROTACs achieve in vivo dose-dependent protein degradation up to 79 % and tumor growth inhibition in A549 and LNCap xenograft mice models, respectively. Taking advantages of in situ self-assembly strategy, the Nano-PROTACs provide a generalizable platform to promote precise clinical translational application of PROTAC.     

Orderly Self-Assembly of Organic Fluorophores for Sensing and Imaging

Fluorescence imaging utilizing traditional organic fluorophores is extensively applied in both cellular and in vivo studies. However, it faces significant obstacles, such as low signal-to-background ratio (SBR) and spurious positive/negative signals, primarily due to the facile diffusion of these fluorophores. To cope with this challenge, orderly self-assembled functionalized organic fluorophores have gained significant attention in the past decades. These fluorophores can create nanoaggregates via a well-ordered self-assembly process, thus prolonging their residency time within cells and in vivo settings. The development of self-assembled-based fluorophores is an emerging field, and as such, in this review, we present a summary of the progress and challenges of self-assembly fluorophores, focusing on their development history, self-assembly mechanisms, and biomedical applications. We hope that the insights provided herein will assist scientists in further developing functionalized organic fluorophores for in situ imaging, sensing, and therapy.     

Self-assembly Mechanism and Chiral Transfer in CuO Superstructures

Chiral inorganic superstructures have received considerable interest due to the chiral communication between inorganic compounds and chiral organic additives. However, the demanding fabrication and complex multilevel structure seriously hinder the understanding of chiral transfer and self-assembly mechanisms. Herein, we use chiral CuO superstructures as a model system to study the formation process of hierarchical chiral structures. Based on a simple and mild synthesis route, the time-resolved morphology and the in situ chirality evolution could be easily followed. The morphology evolution of the chiral superstructure involves hierarchical assembly, including primary nanoparticles, intermediate bundles, and superstructure at different growth stages. Successive redshifts and enhancements of the CD signal support chiral transfer from the surface penicillamine to the inorganic superstructure. Full-field electro-dynamical simulations reproduced the structural chirality and allowed us to predict its modulation. This work opens the door to a large family of chiral inorganic materials where chiral molecule-guided self-assembly can be specifically designed to follow a bottom-up chiral transfer pathway.     

A DNA Origami-based Bactericide for Efficient Healing of Infected Wounds

Bacteria infection is a significant obstacle in the clinical treatment of exposed wounds facing widespread pathogens. Herein, we report a DNA origami-based bactericide for efficient anti-infection therapy of infected wounds in vivo. In our design, abundant DNAzymes (G4/hemin) can be precisely organized on the DNA origami for controllable generation of reactive oxygen species (ROS) to break bacterial membranes. After the destruction of the membrane, broad-spectrum antibiotic levofloxacin (LEV, loaded in the DNA origami through interaction with DNA duplex) can be easily delivered into the bacteria for successful sterilization. With the incorporation of DNA aptamer targeting bacterial peptidoglycan, the DNA origami-based bactericide can achieve targeted and combined antibacterial therapy for efficiently promoting the healing of infected wounds. This tailored DNA origami-based nanoplatform provides a new strategy for the treatment of infectious diseases in vivo.     

Two-Dimensional Supramolecular Polymerization of a Bis-Urea Macrocycle into a Brick-Like Hydrogen-Bonded Network

We report on a dendronized bis-urea macrocycle 1 self-assembling via a cooperative mechanism into two-dimensional (2D) nanosheets formed solely by alternated urea-urea hydrogen bonding interactions. The pure macrocycle self-assembles in bulk into one-dimensional liquid-crystalline columnar phases. In contrast, its self-assembly mode drastically changes in CHCl₃ or tetrachloroethane, leading to 2D hydrogen-bonded networks. Theoretical calculations, complemented by previously reported crystalline structures, indicate that the 2D assembly is formed by a brick-like hydrogen bonding pattern between bis-urea macrocycles. This assembly is promoted by the swelling of the trisdodecyloxyphenyl groups upon solvation, which frustrates, due to steric effects, the formation of the thermodynamically more stable columnar macrocycle stacks. This work proposes a new design strategy to access 2D supramolecular polymers by means of a single non-covalent interaction motif, which is of great interest for materials development.     

Sterically Allowed H-type Supramolecular Polymerizations

The functionalization of π-conjugated scaffolds with sterically demanding substituents is a widely used tactic to suppress cofacial (H-type) stacking interactions, which may even inhibit self-assembly. Contrary to expectations, we demonstrate herein that increasing steric effects can result in an enhanced thermodynamic stability of H-type supramolecular polymers. In our approach, we have investigated two boron dipyrromethene (BODIPY) dyes with bulky phenyl ( 2 ) and mesityl ( 3 ) meso-substituents and compared their self-assembly in nonpolar media with that of a parent meso-methyl BODIPY 1 lacking bulky groups. While the enhanced steric demand induces pathway complexity, the superior thermodynamic stability of the H-type pathways can be rationalized in terms of additional enthalpic gain arising from intermolecular C−H⋅⋅⋅F−B interactions of the orthogonally arranged aromatic substituents, which overrule their inherent steric demand. Our findings underline the importance of balancing competing non-covalent interactions in self-assembly.     

A Subtle Change in the Flexible Achiral Spacer Does Matter in Supramolecular Chirality: Two-Fold Odd-Even Effect in Polymer Assemblies

Precise control over the chirality and morphologies of polymer assemblies, a remaining challenge for both chemists and materials scientists, is receiving ever-increasing attention in the recent years. Herein, we report the subtle manipulation of the achiral spacers from the chiral stereocenter to the azobenzene (Azo) unit, of which the chiroptical consistency or chiroptical inversion of self-assemblies could be successfully controlled and present “two-fold” odd-even effect. Furthermore, morphological transitions from 0D spherical micelles, 1D worms, and nanowires to 3D vesicles, spindle- and dumbbell-shaped vesicles were also unexpectedly found to exhibit odd-even correlations. These observations were collectively elucidated by mesomorphic properties, stacking modes, chiroptical dynamics, and stimuli-responsive behaviors. Negligible modifications to the spacer structures can enable remarkable modulation of supramolecular chirality and anisotropic topologies in polymer assemblies, which is of great significance for the design of complex chiral functional polymers.     

Photo-Induced Self-assembly of Copolymer-Capped Nanoparticles into Colloidal Molecules

Colloidal molecules (CMs) are precisely defined assemblies of nanoparticles (NPs) that mimic the structure of real molecules, but externally programming the precise self-assembly of CMs is still challenging. In this work, we show that the photo-induced self-assembly of complementary copolymer-capped binary NPs can be precisely controlled to form clustered AB _x or linear ( AB ) _y CMs at high yield (x is the coordination number of NP- B s, and y is the repeating unit number of AB clusters). Under UV light irradiation, photolabile p-methoxyphenacyl groups of copolymers on NP- A *s are converted to carboxyl groups (NP- A ), which react with tertiary amines of copolymers on NP- B to trigger the directional NP bonding. The x value of AB _x can be precisely controlled between 1 and 3 by varying the irradiation duration and hence the amount of carboxyl groups generated on NP- A s. Moreover, when NP- A * and NP- B are irradiated after mixing, the assembly process generates AB clusters or linear ( AB ) _y structures with alternating sequence of the binary NPs. This assembly approach offers a simple yet non-invasive way to externally regulate the formation of various CMs on demand without the need of redesigning the surface chemistry of NPs for use in drug delivery, diagnostics, optoelectronics, and plasmonic devices.