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Abstract The management of diabetes in a manner offering autonomous insulin therapy responsive to glucose‐directed need, and moreover with a dosing schedule amenable to facile administration, remains an ongoing goal to improve the standard of care. While basal insulins with reduced dosing frequency, even once‐weekly administration, are on the horizon, there is still no approved therapy that offers glucose‐responsive insulin function. Herein, a nanoscale complex combining both electrostatic‐ and dynamic‐covalent interactions between a synthetic dendrimer carrier and an insulin analogue modified with a high‐affinity glucose‐binding motif yields an injectable insulin depot affording both glucose‐directed and long‐lasting insulin availability. Following a single injection, it is even possible to control blood glucose for at least one week in diabetic swine subjected to daily oral glucose challenges. Measurements of serum insulin concentration in response to challenge show increases in insulin corresponding to elevated blood glucose levels, an uncommon finding even in preclinical work on glucose‐responsive insulin. Accordingly, the subcutaneous nanocomplex that results from combining electrostatic‐ and dynamic‐covalent interactions between a modified insulin and a synthetic dendrimer carrier affords a glucose‐responsive insulin depot for week‐long control following a single routine injection. 

Abstract Dynamic hydrogel crosslinking captures network reorganization and self‐healing of natural materials, yet is often accompanied by reduced mechanical properties compared to covalent analogs. Toughening is possible in certain materials with processing by directional freeze‐casting and salting‐out, producing hierarchically organized networks with directionally enhanced mechanical properties. The implications of including dynamic supramolecular crosslinking alongside such processes are unclear. Here, a supramolecular hydrogel prepared from homoternary crosslinking by pendant guests with a free macrocycle is subsequently processed by directional freeze‐casting and salting‐out. The resulting hydrogels tolerate multiple cycles of compression. Excitingly, supramolecular affinity dictates the mechanical properties of the bulk hydrogels, with higher affinity interactions producing materials with higher Young's modulus and enhanced toughness under compression. The importance of supramolecular crosslinking is emphasized with a supramolecular complex that is converted in situ into a covalent crosslink. While supramolecular hydrogels do not fracture and spontaneously self‐heal when cut, their covalent analogs fracture under moderate strain and do not self‐heal. This work shows a molecular‐scale origin of bulk hydrogel toughening attributed to affinity and dynamics of supramolecular crosslinking, offering synergy in combination with bulk post‐processing techniques to yield materials with enhanced mechanical properties tunable at the molecular scale for the needs of specific applications. 

Abstract Diabetes is one of the most pressing healthcare challenges facing society. Dysfunctional insulin signaling causes diabetes, leading to blood glucose instability and many associated complications. While the administration of exogenous insulin is then essential for achieving glucose control, issues with dosing accuracy and timing remain. Hydrogel‐based drug delivery systems have been broadly explored for controlled protein release, including for applications in long‐lasting and oral insulin delivery. More recently, efforts have focused on injectable hydrogels with glucose‐directed controlled release of insulin and glucagon, aiming for more autonomous and biomimetic approaches to blood glucose control. These materials typically use protein‐based sensing mechanisms or glucose binding by synthetic aryl boronates for glucose‐directed release. Despite advancements in this area, there remains a need for more precise timing of therapeutic availability to afford healthy blood glucose homeostasis, providing an opportunity for further research and innovation. This review summarizes the current state of hydrogel‐based delivery of insulin and glucagon, with insights into the potential benefits, future directions, and challenges that must be overcome to achieve clinical impact. 

Abstract The combination of multiple orthogonal interactions enables hierarchical complexity in self‐assembled nanoscale materials. Here, efficient supramolecular polymerization of DNA origami nanostructures is demonstrated using a multivalent display of small molecule host–guest interactions. Modification of DNA strands with cucurbit[7]uril (CB[7]) and its adamantane guest, yielding a supramolecular complex with an affinity of order 10¹⁰m⁻¹, directs hierarchical assembly of origami monomers into 1D nanofibers. This affinity regime enables efficient polymerization; a lower‐affinity β‐cyclodextrin–adamantane complex does not promote extended structures at a similar valency. Finally, the utility of the high‐affinity CB[7]–adamantane interactions is exploited to enable responsive enzymatic actuation of origami nanofibers assembled using peptide linkers. This work demonstrates the power of high‐affinity CB[7]–guest recognition as an orthogonal axis to drive self‐assembly in DNA nanotechnology. 

Abstract In an effort to augment the function of supramolecular biomaterials, recent efforts have explored the creation of hybrid materials that couple supramolecular and covalent components. Here, the benzenetricarboxamide (BTA) supramolecular polymer motif is modified to present a phenylboronic acid (PBA) in order to promote the crosslinking of 1D BTA stacks by PBA–diol dynamic‐covalent bonds through the addition of a multi‐arm diol‐bearing crosslinker. Interestingly, the combination of these two motifs serves to frustrate the resulting assembly process, yielding hydrogels with worse mechanical properties than those prepared without the multi‐arm diol crosslinker. Both systems with and without the crosslinker do, however, respond to the presence of a physiological level of glucose with a reduction in their mechanical integrity; repulsive electrostatic interactions in the BTA stacks occur in both cases upon glucose binding, with added competition from glucose with PBA–diol bonds amplifying glucose response in the hybrid material. Accordingly, the present results point to an unexpected outcome of reduced hydrogel mechanics, yet increased glucose response, when two disparate dynamic motifs of BTA supramolecular polymerization and PBA–diol crosslinking are combined, offering a vision for future preparation of glucose‐responsive supramolecular biomaterials. 

Abstract The transient self‐assembly of molecules under the direction of a consumable fuel source is fundamental to biological processes such as cellular organization and motility. Such biomolecular assemblies exist in an out‐of‐equilibrium state, requiring continuous consumption of high energy molecules. At the same time, the creation of bioinspired supramolecular hydrogels has traditionally focused on associations occurring at the thermodynamic equilibrium state. Here, hydrogels are prepared from cucurbit[7]uril host–guest supramolecular interactions through transient physical crosslinking driven by the consumption of a reactive chemical fuel. Upon action from this fuel, the affinity and dynamics of CB[7]–guest recognition are altered. In this way, the lifetime of transient hydrogel formation and the dynamic modulus obtained are governed by fuel consumption, rather than being directed by equilibrium complex formation. 

Host–guest interactions have been increasingly explored for use in the dynamic physical crosslinking of polymeric precursors to form hydrogel networks. However, the orientation of guest motifs is restricted upon macromolecule conjugation. The implications of such restriction on both the kinetics and thermodynamics of the resulting host–guest supramolecular crosslinks are poorly understood. Herein, guest crosslinking motifs from controlled regioisomers are demonstrated to yield distinct material properties. Moreover, the underlying phenomena point to further unexpected impact of modular guest topology manifest on the molecular scale in both the affinity and dynamics of supramolecular complex formation. 

Glucose-responsive hydrogel systems are increasingly explored for insulin delivery, with dynamic-covalent crosslinking interactions between phenylboronic acids (PBA) and diols forming a key glucose-sensing mechanism. However, commonly used PBA and diol chemistries often have limited responsiveness to glucose under physiological concentrations. This is due, in part, to the binding of PBA to the commonly used diol chemistries having higher affinity than for PBA to glucose. The present study addresses this challenge by redesigning the diol chemistry in an effort to reduce its binding affinity to PBA, thereby enhancing the ability of glucose to compete with these redesigned PBA–diol crosslinks at its physiological concentration, thus improving responsiveness of the hydrogel network. Rheological analyses support enhanced sensitivity of these PBA–diol networks to glucose, while insulin release likewise improves from networks with reduced crosslink affinities. This work thus offers a new molecular design approach to improve glucose-responsive hydrogels for insulin delivery in diabetes management. 

This study investigates the development of a supramolecular peptide amphiphile (PA) material functionalized with phenylboronic acid (PBA) for glucose-responsive glucagon delivery. The PA-PBA system self-assembles into nanofibrillar hydrogels in the presence of physiological glucose levels, resulting in stable hydrogels capable of releasing glucagon under hypoglycemic conditions. Glucose responsiveness is driven by reversible binding between PBA and glucose, which modulates the electrostatic interactions necessary for hydrogel formation and dissolution. Through comprehensive in vitro characterization, including circular dichroism, zeta potential measurements, and rheological assessments, the PA-PBA system is found to exhibit glucose-dependent assembly, enabling controlled glucagon release that is inversely related to glucose concentration. Glucagon release is accelerated under low glucose conditions, simulating a hypoglycemic state, with a reduced rate seen at higher glucose levels. Evaluation of the platform in vivo using a type 1 diabetic mouse model demonstrates efficacy in protecting against insulin-induced hypoglycemia by restoring blood glucose levels following an insulin overdose. The ability to tailor glucagon release in response to fluctuating glucose concentrations underscores the potential of this platform for improving glycemic control. These findings suggest that glucose-stabilized supramolecular peptide hydrogels hold significant promise for responsive drug delivery applications, offering an approach to manage glucose levels in diabetes and other metabolic disorders. 

A need to enhance the precision and specificity of therapeutic nanocarriers inspires the development of advanced nanomaterials capable of sensing and responding to disease-related cues. Self-assembled peptides offer a promising nanocarrier platform with versatile use to create precisely defined nanoscale materials. Disease-relevant cues can range from large biomolecules, such as enzymes, to ubiquitous small molecules with varying concentrations in healthy versus diseased states. Notably, pH changes (i.e., H+ concentration), redox species (e.g., H2O2), and glucose levels are significant spatial and/or temporal indicators of therapeutic needs. Self-assembled peptides respond to these cues by altering their solubility, modulating electrostatic interactions, or facilitating chemical transformations through dynamic or labile bonds. This review explores the design and construction of therapeutic nanocarriers using self-assembled peptides, focusing on how peptide sequence engineering and the inclusion of non-peptidic components can link the assembly state of these nanocarriers to the presence of disease-relevant small molecules.