A modular route to prepare functional self-assembling dendritic peptide amphiphiles decorated with mannosides, to effectively target antigen-presenting cells, such as macrophages, is reported. The monomeric building blocks were equipped with tetra(ethylene glycol)s (TEGs) or labeled with a Cy3 fluorescent probe. Experiments on the uptake of the multifunctional supramolecular particles into murine macrophages (Mφs) were monitored by confocal microscopy and fluorescence-activated cell sorting. Mannose-decorated supramolecular polymers trigger a significantly higher cellular uptake and distribution, relative to TEG carrying bare polymers. No cytotoxicity or negative impact on cytokine production of the treated Mφs was observed, which emphasized their biocompatibility. The modular nature of the multicomponent supramolecular polymer coassembly protocol is a promising platform to develop fully synthetic multifunctional vaccines, for example, in cancer immunotherapy.

Tumor-associated macrophages (TAMs) promote the immune suppressive microenvironment inside tumors and are, therefore, considered as a promising target for the next generation of cancer immunotherapies. To repolarize their phenotype into a tumoricidal state, the Toll-like receptor 7/8 agonist imidazoquinoline IMDQ is site-specifically and quantitatively coupled to single chain antibody fragments, so-called nanobodies, targeting the macrophage mannose receptor (MMR) on TAMs. Intravenous injection of these conjugates result in a tumor-and cell-specific delivery of IMDQ into MMR high TAMs, causing a significant decline in tumor growth. This is accompanied by a repolarization of TAMs towards a pro-inflammatory phenotype and an increase in anti-tumor T cell responses. Therefore, the therapeutic benefit of such nanobody-drug conjugates may pave the road towards effective macrophage re-educating cancer immunotherapies.

Tumor-associated carbohydrate antigens are overexpressed as altered-self in most common epithelial cancers. Their glycosylation patterns differ from those of healthy cells, functioning as an ID for cancer cells. Scientists have been developing anti-cancer vaccines based on mucin glycopeptides, yet the interplay of delivery system, adjuvant and tumor associated MUC epitopes in the induced immune response is not well understood. The current state of the art suggests that the identity, abundancy and location of the glycans on the MUC backbone are all key parameters in the cellular and humoral response. This review shares lessons learned by us in over two decades of research in glycopeptide vaccines. By bridging synthetic chemistry and immunology, we discuss efforts in designing synthetic MUC1/4/16 vaccines and focus on the role of glycosylation patterns. We provide a brief introduction into the mechanisms of the immune system and aim to promote the development of cancer subunit vaccines.

A multistimuli‐responsive supramolecular copolymerization is reported. The copolymerization is driven by hydrogen bond encoded β‐sheet‐based charge co‐assembly into 1D nanorods in water, using glutamic acid or lysine residues in either of the peptide comonomers. The incorporation of methionine as hydrophobic amino acid supports β‐sheet formation, but oxidation of the thioether side‐chain to a sulfoxide functional group destabilizes the β‐sheet ordered domains and induces disassembly of the supramolecular polymers. Using H2O2 as reactive oxygen species, the time scale and kinetics of the oxidative disassembly are probed. Compared to the charge neutral homopolymers, it is found that the oxidative disassembly of the charged ampholytic copolymers is up to two times faster and is operative at neutral pH. The strategy is therefore an important addition to the growing field of amphiphilic polythioether containing (macro)molecular building blocks, particularly in view of tuning their oxidation induced disassembly which tends to be notoriously slow and requires high concentrations of reactive oxygen species or acidic reaction media.

Mucin expression and glycosylation patterns on cancer cells differ markedly from healthy cells. Mucin 1 (MUC1) is overexpressed in several solid tumors and presents high levels of aberrant, truncated O-glycans (e.g., Tn antigen). Dendritic cells (DCs) express lectins that bind to these tumor-associated carbohydrate antigens (TACAs) to modulate immune responses. Selectively targeting these receptors with synthetic TACAs is a promising strategy to develop anticancer vaccines and to overcome TACA tolerance. In this work, we prepared, via a solid phase peptide synthesis approach, a modular tripartite vaccine candidate, incorporating a high-affinity glycocluster based on a tetraphenylethylene scaffold, to target the macrophage galactose-type lectin (MGL) on antigen presenting cells. MGL is a C-type lectin receptor that binds Tn antigens and can route them to human leukocyte antigen class II or I, making it an attractive target for anticancer vaccines. Conjugation of the glycocluster to a library of MUC1 glycopeptides bearing the Tn antigen is shown to promote uptake and recognition of the TACA by DCs via MGL. In vivo testing revealed that immunization with the newly designed vaccine construct bearing the GalNAc glycocluster induced a higher titer of anti-Tn-MUC1 antibodies compared to the TACAs alone. Additionally, the antibodies obtained bind a library of tumor-associated saccharide structures on MUC1 and MUC1-positive breast cancer cells. Conjugation of a high-affinity ligand for MGL to tumorassociated MUC1 glycopeptide antigens has a synergistic impact on antibody production.

Glycopeptide supramolecular polymers displaying multivalent carbohydrates are particularly suitable for immune-relevant biomaterials, due to the important functions of carbohydrates in mediating cell-cell communication and modulating immune responses. However, the diversity and complexity of carbohydrates limited the generation of glycopeptide supramolecular monomers. Thereby, a modular platform of presenting various carbohydrates, especially more complex oligosaccharides, is highly desirable but remains underexplored. Here, we first prepared the linear amphiphilic glycopeptides that self-assembled into spherical nanoparticles and worm-like nanoparticles. Furthermore, the dendritic glycopeptides that self-assembled into uniform nanorods were designed to generate modular supramolecular polymers with variable functionality, via redesigning the molecular backbone. With various functional oligosaccharide-modified supramolecular polymers, the in vitro studies further indicated that these polymers were not cytotoxic to macrophages, and significantly modulated the production of proinflammatory cytokines. These findings provide a promising platform to develop supramolecular glycopeptide biomaterials with potential applications in immunomodulation and immunotherapy.

Temperature-responsive polyurethane (PU) hydrogels represent a versatile material platform for modern tissue engineering and biomedical applications. However, besides intrinsic advantages such as high mechanical strength and a hydrolysable backbone composition, plain PU materials are generally lacking bio-adhesive properties. To overcome this shortcoming, the authors focus on the synthesis of thermoresponsive PU hydrogels with variable mechanical and cell adhesive properties obtained from linear precursor PUs based on poly(ethylene glycol)s (pEG) with different molar masses, isophorone diisocyanate, and a dimerizable dimethylmaleimide (DMMI)-diol. The cloud point temperatures of the dilute, aqueous PU solutions depend linearly on the amphiphilic balance. Rheological gelation experiments under UV-irradiation reveal the dependence of the gelation time on photosensitizer concentration and light intensity, while the finally obtained gel strength is determined by the polymer concentration and spacing of the crosslinks. The swelling ratios of these soft hydrogels show significant changes between 5 and 40 °C whereby the extent of this switch increases with the hydrophobicity of the precursor. Moreover, it is shown that the incorporation of a low amount of catechol groups into the networks through the DMMI dimerization reaction leads to strongly improved cell adhesive properties without significantly weakening the gels.

The combination of complementary, noncovalent interactions is a key principle for the design of multistimuli responsive hydrogels. In this work, an amphiphilic peptide, supramacromolecular hydrogelator which combines metal-ligand coordination induced gelation and thermoresponsive toughening is reported. Following a modular approach, the incorporation of the triphenylalanine sequence FFF into a structural (C 3 EG ) and a terpyridine-functionalized (C 3 Tpy ) C 3 -symmetric monomer enables their statistical copolymerization into self-assembled, 1D nanorods in water, as investigated by circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM). In the presence of a terpyridine functionalized telechelic polyethylene glycol (PEG) cross-linker, complex formation upon addition of different transition metal ions (Fe 2+ , Zn 2+ , Ni 2+ ) induces the formation of soft, reversible hydrogels at a solid weight content of 1 wt% as observed by linear shear rheology. The viscoelastic behavior of Fe 2+ and Zn 2+ cross-linked hydrogels are basically identical, while the most kinetically inert Ni 2+ coordinative bond leads to significantly weaker hydrogels, suggesting that the most dynamic rather than the most thermodynamically stable interaction supports the formation of robust and responsive hydrogel materials.