Stimuli-responsive hydrogels are intriguing biomaterials useful for spatiotemporal controlled release of drugs, cells, and biological cues, cell engineering for various applications, and medical diagnosis. To date, many physical and chemical stimuli-responsive polymer hydrogels have been developed by chemical modification of polymer chains and cross-linking points. In particular, conjugation with biomolecules to polymers produced promising biomolecule-responsive hydrogels. These examples clearly indicate high potentials of stimuli-responsive hydrogels as promising biomaterials. In addition to polymer hydrogels, supramolecular hydrogels formed by the assembly of small molecules (hydrogelators) via noncovalent interactions have also been regarded as unique and promising soft materials due to their flexible programmability in rendering them stimuli-responsive with the larger macroscopic change (i.e., gel-sol transition). This Account describes our strategies for the rational design of stimuli-responsive supramolecular hydrogels and their biological applications. Following the detailed structural analysis of a lead hydrogelator that clearly indicates the appropriate sites for incorporation of stimuli-responsive modules, we designed supramolecular hydrogels capable of responding to simple physical (thermal and light) and chemical (pH and metal ions) stimuli. More importantly, biomolecule-responsive hydrogels were successfully developed by supramolecularly mimicking the complex yet well-ordered structures and functions of live cells containing multiple components (a cell-mimicking approach). Development of biomolecule-responsive supramolecular hydrogels has been difficult as the conventional strategy relies on the chemical incorporation of stimuli-responsive modules, owing to the lack of modules that can effectively respond to structurally diverse and complicated biomolecules. Inspired by natural systems where functional compartments (e.g., cell organelles) sophisticatedly interact with each other, we sought to integrate the two distinct microenvironments of supramolecular hydrogels (the aqueous cavity surrounded by fibers and the fluidic hydrophobic fiber domain) with other functional materials (e.g., enzymes, peptides or proteins, fluorescent chemosensors, or inorganic porous or layered nanomaterials) for biomolecule responses. In situ fluorescence microscopy imaging clearly demonstrated that chemical isolation and crosstalk are highly successful between the integrated microenvironments in supramolecular hydrogels, similar to organelles in living cells, which allow for the construction of unique optical response and sensing systems for biomolecules. Furthermore, programmed hybridization of our chemically reactive hydrogels with appropriate enzymes can provide an unprecedented universal platform for biomolecule-degradable supramolecular hydrogels. Such biomolecule-responsive hydrogels are a potentially promising tool for user-friendly early diagnostics and on-demand drug-releasing soft materials. We expect that our ra...

Self-sorted supramolecular nanofibres-a multicomponent system that consists of several types of fibre, each composed of distinct building units-play a crucial role in complex, well-organized systems with sophisticated functions, such as living cells. Designing and controlling self-sorting events in synthetic materials and understanding their structures and dynamics in detail are important elements in developing functional artificial systems. Here, we describe the in situ real-time imaging of self-sorted supramolecular nanofibre hydrogels consisting of a peptide gelator and an amphiphilic phosphate. The use of appropriate fluorescent probes enabled the visualization of self-sorted fibres entangled in two and three dimensions through confocal laser scanning microscopy and super-resolution imaging, with 80 nm resolution. In situ time-lapse imaging showed that the two types of fibre have different formation rates and that their respective physicochemical properties remain intact in the gel. Moreover, we directly visualized stochastic non-synchronous fibre formation and observed a cooperative mechanism.

Novel soft materials should comprise multiple supramolecular nanostructures whose responses (for example, assembly and disassembly) to external stimuli can be controlled independently. Such multicomponent systems are present in living cells and control the formation and break-up of a variety of supramolecular assemblies made of proteins, lipids, DNA and RNA in response to external stimuli; however, artificial counterparts are challenging to make. Here, we present a hybrid hydrogel consisting of a self-sorting double network of nanofibres in which each network responds to an applied external stimulus independent of the other. The hydrogel can be made to change its mechanical properties and rates of release of encapsulated proteins by adding NaSO or bacterial alkaline phosphatase. Notably, the properties of the gel depend on the order in which the external stimuli are applied. Multicomponent hydrogels comprising orthogonal stimulus-responsive supramolecular assemblies would be suitable for designing novel adaptive materials.

Multicomponent supramolecular hydrogels are constructed for sensitive, naked-eye detection of small-molecule biomarkers. A dendritic self-immolative molecule and the corresponding enzyme as a signal amplification system were stably embedded in a hydrogen peroxide (H2O2)-responsive supramolecular hydrogel (BPmoc-F3), together with other enzymes. The nanostructure and mechanical strength of the hybrid BPmoc-F3 gel were not substantially diminished by incorporation of these multiple components in the absence of target biomarkers, but could be destroyed by addition of the biomarker through the multiple enzymatic and chemical cascade reactions operating in combination within the gel matrix. The sensitivity to biomarkers such as H2O2, glucose, and uric acid, detected by gel-sol transition, was significantly enhanced by the signal amplification system. An array chip consisting of these multicomponent hydrogels enabled the detection of the level of hyperuricemia disease in human plasma samples.

Non-enzymatic proteins including antibodies function as biomarkers and are used as biopharmaceuticals in several diseases. Protein-responsive soft materials capable of the controlled release of drugs and proteins have potential for use in next-generation diagnosis and therapies. Here, we describe a supramolecular/agarose hydrogel composite that can release a protein in response to a non-enzymatic protein. A non-enzymatic protein-responsive system is developed by hybridization of an enzyme-sensitive supramolecular hydrogel with a protein-triggered enzyme activation set. In situ imaging shows that the supramolecular/ agarose hydrogel composite consists of orthogonal domains of supramolecular fibers and agarose, which play distinct roles in protein entrapment and mechanical stiffness, respectively. Integrating the enzyme activation set with the composite allows for controlled release of the embedded RNase in response to an antibody. Such composite hydrogels would be promising as a matrix embedded in a body, which can autonomously release biopharmaceuticals by sensing biomarker proteins.

To develop a novel pi-conjugated molecule-based supramolecular assembly, we designed and synthesized trisdehydrotribenzo[12]annulene ([12]DBA) derivative 2 with three carboxyl groups at the periphery. Recrystallization of 2 from DMSO gave a crystal of the solvate 23 DMSO. Crystallographic analysis revealed, to our surprise, that a face-to-face pi-stacked one-dimensional (1D) assembly of 2 was achieved and that the DMSO molecule played a significant role as a "structure-dominant element" in the crystal. This is the first example of [12]DBA to stack completely orthogonal to the columnar axis. To reveal its superstructure-dependent optical and electrical properties, 2 and its parent molecule 1, which crystallizes in a herringbone fashion, were subjected to fluorescence spectroscopic analysis and charge-carrier mobility measurements in crystalline states. The 1D stacked structure of 2 provides a red-shifted, broadened, weakened fluorescence profile (lambda(max) = 545 nm, phi(F) = 0.01), compared to 1 (lambda(max) = 491 nm, phi(F) = 0.12), due to strong interactions between the p orbitals of the stacked molecules. The charge-carrier mobility of the single crystal of 23 DMSO, as well as 1, was determined by flash photolysis time-resolved microwave conductivity (FP-TRMC) measurements. The single crystal of 23 DMSO revealed significantly-anisotropic charge mobility (sigma(mu) = 1.5x10(-1) cm(2) V(-1) s(-1)) along the columnar axis (crystallographic c axis). This value is 12 times larger than that along the orthogonal axis (the a axis).

Living cells exhibit sophisticated functions because they contain numerous endogenous stimuli-responsive molecular systems that independently and cooperatively act in response to an external circumstance. On the other hand, artificial soft materials containing multiple stimuli-responsive molecular systems are still rare. Herein, we demonstrate a unique multicomponent hydrogel composed of a self-sorting double network prepared through a post-assembly fabrication (PAF) protocol. The PAF protocol allowed the construction of a well-ordered hydrogel with a dual-biomolecule response to two important biomolecules (adenosine triphosphate (ATP) and sarcosine). Such a hydrogel could not be prepared through a one-step mixing protocol. The resultant multicomponent hydrogel responded to ATP and sarcosine through gel–sol transition behavior programmed in an AND logic gate fashion. Finally, we applied the multicomponent hydrogel to the controlled release of an antibody.

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