This work illustrates a strategy for the design of molecularly defined immunotherapies, using a blend of supramolecular peptide self‐assembly and active site‐directed protein capture.

Glycosylation alters protein form and function by establishing intermolecular forces that mediate specific interactions while preventing non-specific aggregation. Self-assembled peptide nanofibers modified with carbohydrates are increasingly used as biomaterials to mimic glycosylated protein function, yet the influence of carbohydrate conjugates on nanofiber structure remains poorly defined. Here we show that a dense carbohydrate surface layer can facilitate hierarchical organization of peptide nanofibers into anisotropic networks. Glycosylated peptide nanofibers remain dispersed in dilute conditions, whereas non-glycosylated nanofibers tend to aggregate. In crowded conditions, some glycosylated nanofibers laterally associate and align. This behavior depends on carbohydrate chemistry, particularly hydroxyls, suggesting involvement of short-range attractive forces. Macroscopic gels fabricated from densely glycosylated peptide nanofibers are resistant to non-specific interactions with proteins, mammalian cells, and bacteria, yet selectively bind lectins, analogous to natural low-fouling mucosal barriers. Collectively, these observations demonstrate that glycosylation can inform structure in addition to endowing function to peptide-based supramolecular biomaterials.

Significance: The family of carbohydrate-binding proteins known as galectins receive considerable attention for their ability to modulate cell behavior in both normal and pathological settings. Galectin-3, for instance, can crosslink membrane glycans to initiate, amplify, attenuate, or inhibit signal transduction pathways that lead to cell differentiation, proliferation, or death. However, understanding structure–function relationships of galectin-3 is challenged by its promiscuous glycan-binding properties and assembly into oligomers with undefined number of subunits or “valency.” Here, we address these challenges by providing a toolbox of synthetic galectin-3 oligomers with tunable valency. Cell-based studies with these oligomers suggest a role for physical size as a structural determinant of galectin-3 signaling function, in addition to the increased binding strength typically associated with multivalency.

Throughout nature, self-assembly gives rise to functional supramolecular biomaterials that can perform complex tasks with extraordinary efficiency and specificity. Inspired by these examples, self-assembly is increasingly used to fabricate synthetic supramolecular biomaterials for diverse applications in biomedicine and biotechnology. Peptides are particularly attractive as building blocks for these materials because they are based on naturally derived amino acids that are biocompatible and biodegradable; they can be synthesized using scalable and cost-effective methods, and their sequence can be tailored to encode formation of diverse architectures. To endow synthetic supramolecular biomaterials with functional capabilities, it is now commonplace to conjugate self-assembling building blocks to molecules having a desired functional property, such as selective recognition of a cell surface receptor or soluble protein, antigenicity, or enzymatic activity. This review surveys recent advances in using self-assembling peptides as handles to incorporate biologically active molecules into supramolecular biomaterials. Particular emphasis is placed on examples of functional nanofibers, nanovesicles, and other nano-scale structures that are fabricated by linking self-assembling peptides to proteins and carbohydrates. Collectively, this review highlights the enormous potential of these approaches to create supramolecular biomaterials with sophisticated functional capabilities that can be finely tuned to meet the needs of downstream applications.