Jeongyun Heo

In the native extracellular matrix, collagen fibrils regulate stem cell fate and tissue regeneration by modulating the number of serial kinks via intramolecular kinking and unkinking, which affects integrin ligation. However, biomimetic materials composed solely of multi‐kink‐bearing molecules for dynamic regulation of ligand exposure remain limited. In this study, we designed materials composed solely of liganded multiple kink‐bearing molecules with a tunable number of kink points (mono‐kink, tri‐kink, and penta‐kink molecules), including flexible linkers and densely packed via intermolecular interactions, are designed. Near‐infrared‐upconverted ultraviolet light and visible light induce multiple kinking and unkinking of liganded multiple kink‐bearing molecules conjugated to upconversion nanoparticle‐coated materials, inducing kinked and unkinked states, respectively. Tri‐kinking and unkinking mediate the effective regulation of ligand masking and exposure, respectively, by modulating intermolecular interactions, while mono‐kink and penta‐kink molecules continuously expose the ligands regardless of their kinking/unkinking state. Tri‐unkinking cyclically stimulates integrin ligation and focal adhesion‐mediated stem cell mechanotransduction and differentiation in vivo, which are inhibited by tri‐kinking. This study presents a newly developed reversibly switchable multi‐kink molecule‐conjugated surface for dynamic regulation of ligand exposure and stem cell responses, providing a useful modality for regulating cell–material interactions and stem cell fate in vivo.

Dynamic manipulation of supramolecular self‐assembled structures is achieved irreversibly or under non‐physiological conditions, thereby limiting their biomedical, environmental, and catalysis applicability. In this study, microgels composed of azobenzene derivatives stacked via π–cation and π–π interactions are developed that are electrostatically stabilized with Arg–Gly–Asp (RGD)‐bearing anionic polymers. Lateral swelling of RGD‐bearing microgels occurs via cis‐azobenzene formation mediated by near‐infrared‐light‐upconverted ultraviolet light, which disrupts intermolecular interactions on the visible‐light‐absorbing upconversion‐nanoparticle‐coated materials. Real‐time imaging and molecular dynamics simulations demonstrate the deswelling of RGD‐bearing microgels via visible‐light‐mediated trans‐azobenzene formation. Near‐infrared light can induce in situ swelling of RGD‐bearing microgels to increase RGD availability and trigger release of loaded interleukin‐4, which facilitates the adhesion structure assembly linked with pro‐regenerative polarization of host macrophages. In contrast, visible light can induce deswelling of RGD‐bearing microgels to decrease RGD availability that suppresses macrophage adhesion that yields pro‐inflammatory polarization. These microgels exhibit high stability and non‐toxicity. Versatile use of ligands and protein delivery can offer cytocompatible and photoswitchable manipulability of diverse host cells.

Molecular aggregates are receiving tremendous attention, demonstrating immense potential for biomedical applications in vitro and in vivo. For instance, the molecular aggregates of conventional fluorophores influence the electronic excitation states of the aggregates, causing characteristic photophysical property changes. A fundamental understanding of this classical relationship between molecular aggregate structures and photophysics has allowed for innovative biological applications. The chemical characteristics of drug molecules generally trigger the formation of colloidal aggregates, and this is considered detrimental to the drug discovery process. Furthermore, nano‐sized supramolecular aggregates have been used in biomedical imaging and therapy owing to their optimal properties for in vivo utility, including enhanced cell permeability, passive tumor targeting, and convenient surface engineering. Herein, we provide an overview of the recent trends in molecular aggregates for biomedical applications. The changes in photophysical properties of conventional fluorophores and their biological applications are discussed, followed by the effects of conventional drug molecule‐aggregates on drug discovery and therapeutics development. Recent trends in the investigation of biologically important analytes with aggregation‐induced emission are discussed for conventional and unconventional fluorophores. Lastly, we discuss nano‐sized supramolecular aggregates used in imaging and therapeutic purposes, with a focus on in vivo utilization.

Since oxidative stress has been recognized as a major factor contributing to the progression of several neurodegenerative disorders, reactive oxygen species (ROS) including superoxide have received great attention as a representative molecular marker for the diagnosis of Alzheimer's disease (AD). Here, superoxide-sensitive fluorogenic molecular probes, benzenesulfonylated resorufin derivatives (BSRs), were newly devised for optical bioimaging of oxidative events in neurodegenerative processes. BSRs, fluorescence-quenched benzenesulfonylated derivatives of resorufin, were designed to recover their fluorescence upon exposure to superoxide through a selective nucleophilic uncaging reaction of the benzenesulfonyl cage. Among BSRs, BSR6 presented the best sensitivity and selectivity to superoxide likely due to the optimal reactivity matching between the nucleophilicity of superoxide and its electrophilicity ascribed to the highly electron-withdrawing pentafluoro-substitution on the benzenesulfonyl cage. Fluorescence imaging of inflammatory cells and animal models presented the potential of BSR6 for optical sensing of superoxide in vitro and in vivo. Furthermore, microglial cell (Bv2) imaging with BSR6 enabled the optical monitoring of intracellular oxidative events upon treatment with an oxidative stimulus (amyloid beta, Aβ) or the byproduct of oxidative stress (4-hydroxynonenal, HNE).