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Abstract Synthetic opioids, especially fentanyl and its analogs, have created an epidemic of abuse and significantly increased overdose deaths in the United States. Current detection methods have drawbacks in their sensitivity, scalability, and portability that limit field‐based application to promote public health and safety. The need to detect trace amounts of fentanyl in complex mixtures with other drugs or interferents, and the continued emergence of new fentanyl analogs, further complicates detection. Accordingly, there is an urgent need to develop convenient, rapid, and reliable sensors for fentanyl detection. In this study, a sensor is prepared based on competitive displacement of a fluorescent dye from the cavity of a supramolecular macrocycle, with subsequent fluorescence quenching from graphene quantum dots. This approach can detect and quantify small quantities of fentanyl along with 58 fentanyl analogs, including highly potent variants like carfentanil that are of increasing concern. Detection of these agents is possible even at 0.01 mol% in the presence of common interferents. This simple, rapid, reliable, sensitive, and cost‐effective approach couples supramolecular capture with graphene quantum dot nanomaterial quenchers to create a tool with the potential to advance public health and safety in the context of field‐based detection of drugs in the fentanyl class. 

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 transient mechanism to achieve gelation in host–guest supramolecular hydrogels is demonstrated by acidification and pH correctionviaindirect control from a biocatalytic enzyme network. 

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. 

Hydrogels comprise a class of soft materials which are extremely useful in a number of contexts, for example as matrix-mimetic biomaterials for applications in regenerative medicine and drug delivery. One particular subclass of hydrogels consists of materials prepared through non-covalent physical crosslinking afforded by supramolecular recognition motifs. The dynamic, reversible, and equilibrium-governed features of these molecular-scale motifs often transcend length-scales to endow the resulting hydrogels with these same properties on the bulk scale. In efforts to engineer hydrogels of all types with more precise or application-specific uses, inclusion of stimuli-responsive sol–gel transformations has been broadly explored. In the context of biomedical uses, temperature is an interesting stimulus which has been the focus of numerous hydrogel designs, supramolecular or otherwise. Most supramolecular motifs are inherently temperature-sensitive, with elevated temperatures commonly disfavoring motif formation and/or accelerating its dissociation. In addition, supramolecular motifs have also been incorporated for physical crosslinking in conjunction with polymeric or macromeric building blocks which themselves exhibit temperature-responsive changes to their properties. Through molecular-scale engineering of supramolecular recognition, and selection of a particular motif or polymeric/macromeric backbone, it is thus possible to devise a number of supramolecular hydrogel materials to empower a variety of future biomedical applications. 

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.