Supramolecular host-guest chemistry can tune the photophysical behavior of organic emitters by confining them within well-defined nanoscale environments. Here we report a straightforward strategy to modulate the thermally activated delayed fluorescence (TADF) properties of organic emitters in aqueous media through complexation with the macrocyclic host cucurbit[7]uril (CB[7]). Upon formation of the TADF-CB[7] complex, the photoluminescence quantum yield is enhanced due to the suppression of non-radiative decay pathways within the rigid host cavity. Furthermore, host-guest encapsulation was found to accelerate both forward and reverse intersystem crossing, resulting in improved access to the triplet state. In the presence of molecular oxygen, this facilitates an increased generation of cytotoxic singlet oxygen, thereby boosting the efficacy of photodynamic therapy (PDT). These findings provide a promising supramolecular approach to advancing the application of TADF materials in aqueous-phase PDT systems.

Odoribacter splanchnicus, a prominent member of the human gut microbiota, has emerged as a promising next-generation probiotic due to its anti-inflammatory properties and association with intestinal health. While previous studies have demonstrated its ability to attenuate inflammation and protect epithelial integrity, the molecular basis underlying these effects remained elusive. In this study, we provide the first comprehensive structural and functional characterization of the O. splanchnicus lipooligosaccharide (LOS), a major immunomodulatory surface component. NMR spectroscopy and mass spectrometry revealed a heterogeneous LOS structure composed of a mono-phosphorylated tetra- and penta-acylated lipid A backbone and a highly branched, short core oligosaccharide featuring unique residues such as 4-lactylmannose and galactosaminuronic acid. Small-angle X-ray scattering demonstrated that the LOS self-assembles into core-shell spherical micelles, with a large oligosaccharide corona shielding the lipid A, thereby limiting its accessibility to the innate immunity TLR4/MD-2 receptor complex. Accordingly, the O. splanchnicus LOS exhibited minimal TLR4 activation and failed to induce IL-8 secretion in enterocyte cell lines, in stark contrast to proinflammatory Escherichia coli LPS; in addition, it potently antagonized E. coli LPS-induced inflammation. These findings identify the LOS as a key effector of the O. splanchnicus anti-inflammatory phenotype and support its further development as a live biotherapeutic agent.

Intracellular calcium release (ICR) is of fundamental importance for numerous physiological and pathological processes, from cell differentiation to neurotransmitter release and muscle contraction. The ability to precisely control ICR is crucial for understanding cellular signaling mechanisms and developing therapeutic interventions for calcium-related disorders. Light-induced ICR offers numerous advantages over conventional approaches, including superior specificity, precise spatiotemporal control, excellent reproducibility, and minimal invasiveness. Here, we demonstrate that cyanine dyes function as molecular jackhammers (MJHs) to induce ICR in human embryonic kidney (HEK) 293 and immortalized mouse myoblast C2C12 cells through vibronic-driven action (VDA) following red light (640 nm) activation. VDA generates longitudinally and axially coordinated whole-molecule vibrations, enabling mechanical interactions with cells. Structure-activity relationship studies of twenty synthesized MJHs demonstrated that sulfonate-containing derivatives most effectively triggered intracellular calcium release while exhibiting minimal cytotoxicity. Mechanistic studies showed that MJH-induced calcium release operates through the inositol-triphosphate (IP3) pathway rather than reactive oxygen species generation. Finally, we demonstrated light-activated MJH-induced calcium waves in vivo using transgenic Hydra vulgaris expressing a fluorescent calcium indicator. This work establishes MJHs as molecular-scale devices for remote control of cellular signaling, expanding the utility of cyanine dyes for modulating physiological processes with potential therapeutic applications.

Geminal diols are generally unstable and prone to dehydration, yielding carbonyl compounds and making their isolation as discrete species highly challenging. Herein, we report the synthesis, structural characterization, and stability of a series of crystalline, stable, and rigid macrocyclic gem-diols obtained via acid hydrolysis of macrocyclic ketal precursors at −25 °C. Single-crystal X-ray diffraction analysis of these compounds reveals O–C–O bond angles of approximately 111°, along with extensive hydrogen-bonding networks that contribute to stabilizing the gem-diols. Thermogravimetric and hydrolytic analyses reveal a pronounced size-dependent stability trend. Theoretical calculations indicate that the enhanced stability of smaller gem-diol macrocycles stems from their ability to relieve substantial angle strain via sp3 hybridization at the methylene carbon, an effect that diminishes as ring size increases. Based on our experimental and computational results, the inner angle value of the macrocyclic ketone is proposed as a criterion for evaluating the relative stability of macrocyclic ketones versus their gem-diol forms. The photophysical properties of the macrocyclic geminal diols and macrocyclic diketones are also examined. This work broadens the scope of stable geminal diols and provides fundamental insights into their structure–stability relationships, thereby laying the groundwork for the strategic design and synthesis of structurally diverse macrocyclic geminal diols.

Fluorescent flippers have been introduced as small-molecule probes to image physical forces within cell membranes. Despite their popularity and much effort, significant improvements of performance have not been reported since their first design. Now, almost a decade after their introduction, we disclose flipper dendrimers that address the main practical problem with flipper probes: phototoxicity. Flipper dendrimers provide much stronger fluorescence in cells while maintaining responsiveness to changes in membrane tension. This increased effective brightness enables imaging at almost one order of magnitude lower laser power to generate the same fluorescence intensity, thereby reducing phototoxicity and allowing longer monitoring of biological processes. This breakthrough is achieved using large peptide dendrimers that maximize deliverability as Israelachvili-inspired inverted cones. Peptide dendrimers and hydrophobic interfacers modulate fluorescence lifetime and plasma membrane targeting by controlling probe orientation, interdomain distribution, intermembrane transfer and internalization. This supramolecular chemistry strategy to improve performance by engineering probe integration into the environment, rather than the mechanophore itself, is generally applicable.

Boronic acid and ester-caged prodrugs have been widely investigated in cellular-generated hydrogen peroxide triggered release. Although it is well-known that ionizing radiation generates hydrogen peroxide in aqueous solution, using this approach to activate boronic acid or ester-based prodrugs suffers from low H2O2 yields and thus low uncaging efficiency. However, the organochloride peroxyl radical formed from irradiating an aqueous solution of an organochloride may increase the uncaging efficiency. In this study, we used a boronic acid-caged coumarin derivative to quantify the yield of oxidation induced by clinical doses of radiation (less than 8 Gy), and boronic acid-caged gemcitabine to assess the activation of a prodrug upon irradiation. Irradiation of the coumarin derivative in phosphate buffered saline shows a low yield of 0.048 µM per Gy, and the prodrug after irradiation has only limited toxicity to the U87 cell line, indicating limited uncaging. The oxidation of boronic acid can be greatly enhanced by the peroxyl radical generated from irradiation of dilute PBS-organochloride solutions, with the yield increasing to 0.13 µM per Gy. Moreover, the oxidation by peroxyl radical can be catalyzed by N,N-dimethylaniline derivatives, increasing the yield to 0.19 µM per Gy. Clinical dose irradiation of the caged gemcitabine derivative in a solution of PBS with trichloroethanol and 2-(dimethylamino)benzoic acid shows efficient tumor cell killing and a comparable toxicity with that of the parent drug, indicating efficient uncaging.

The disconnect between AI-generated molecules with desirable properties and their synthetic feasibility remains a critical bottleneck in computational discovery of drugs and materials. While generative AI has accelerated the proposal of candidate molecules, many of these structures prove challenging or impossible to synthesize using established chemical reactions. Here, we introduce SynTwins, a novel retrosynthesis-guided molecule design framework that finds synthetically accessible molecular analogs by emulating expert chemists' strategies in three steps: retrosynthesis, searching similar building blocks, and virtual synthesis. Using a search algorithm instead of a stochastic data-driven generator, SynTwins outperforms state-of-the-art machine learning models at exploring synthetically accessible analogs while maintaining high structural similarity to original target molecules. Furthermore, when integrated into existing molecular property-optimization frameworks, our hybrid approach produces synthetically feasible analogs with minimal loss in property scores. Our comprehensive benchmarking across diverse molecular datasets demonstrates that SynTwins effectively bridges the gap between computational design and experimental synthesis, providing a practical solution for accelerating the discovery of synthesizable molecules with desired properties for a wide range of applications.

We disclose herein a mild and efficient organolithium-mediated protocol which enables the chemodivergent transformation of ortho-cresol-derived O-aryl carbamates into diverse molecular structures by simply changing the nature of the reaction medium, working under air and at room temperature. The use of the biobased 2-MeTHF as solvent allows the chemoselective preparation of α-hydroxy arylacetamides in a single synthetic operation with a remarkable functional group tolerance. Our strategy, which exploits the presence of molecular oxygen arising from the use of bench-type aerobic conditions, relies on a one-pot anionic homo-Fries rearrangement/amide enolate autoxidation sequence with two consecutive C–C/C–O bond formation events occurring at the same carbon atom. Furthermore, we also describe the successful use of protic and bioinspired Deep Eutectic Solvents (DESs) as an effective tool to tune the chemoselectivity of the proposed transformation. The fast internal protonolysis of the anion solution, operated by the protic reaction medium, results in an interrupted metalation/rearrangement sequence, enabling the chemoselective preparation of arylacetamides under bench-type aerobic conditions owing to the efficient suppression of the oxidation step.

Recent research has seen growing interest in synthesizing inherently chiral macrocycles, driven by their potential applications in chiral supramolecular chemistry. We present herein our design and synthesis of a series of novel inherently chiral macrocycles. These compounds, termed homo-heteracalixarenes, feature a 1,2-diphenylethyne fragment that replaces one of the aryl-heteroatom-aryl linkages found in classic heteracalix[4]aromatics. De novo macrocyclization of linear achiral substrates via an intramolecular Sonogashira cross-coupling reaction affords the 17- or 18-membered chiral cyclophanes in modest yields with up to 90% ee. The strained bent alkyne moiety within the macrocycle provides a key reactive handle for macrocycle-to-macrocycle derivatization. Further, we showed the unique macrocyclic structures and demonstrated interesting chiroptical properties of the obtained enantioenriched homo-calixarenes and their derivatives.