Matthew I. Gibson

The intracellular delivery of glycans is a significant challenge. Glycan delivery is typically achieved by per‐acetylation necessitating the use of the cytotoxic carrier solvent DMSO, or complex nanoscale delivery devices, to transit across the cell membrane. Here we deploy superchaotropic boron clusters to unlock solvent‐free intracellular delivery of azido‐glycans, as well as trehalose. The cluster B ₁₂ Br ₁₂ ^2– delivered glycans into suspension and adherent cells, enabling successful metabolic oligosaccharide labelling and bioconjugation of glycoproteins, cell surface glycans, and also glycosylated‐RNA. This approach offers a practical and operationally simple solution to the challenge of glycan intracellular delivery and removes the cytotoxic impact of solvents.

The intracellular delivery of glycans is a significant challenge. Glycan delivery is typically achieved by per‐acetylation necessitating the use of the cytotoxic carrier solvent DMSO, or complex nanoscale delivery devices, to transit across the cell membrane. Here we deploy superchaotropic boron clusters to unlock solvent‐free intracellular delivery of azido‐glycans, as well as trehalose. The cluster B ₁₂ Br ₁₂ ^2– delivered glycans into suspension and adherent cells, enabling successful metabolic oligosaccharide labelling and bioconjugation of glycoproteins, cell surface glycans, and also glycosylated‐RNA. This approach offers a practical and operationally simple solution to the challenge of glycan intracellular delivery and removes the cytotoxic impact of solvents.

Triazabutadiene-mediated diazonium electrografting is an electrode modification method that enables stable covalent bonds to be made to a versatile range of electrode materials. In biosensing, a challenge in utilizing diazonium electrografting for immobilizing biorecognition elements has been the chemical incompatibility between these biomolecules and the corrosive grafting conditions often required to generate diazonium cations in situ. This work presents a solution to this problem. We describe the utilization of a heterobifunctional linker molecule that possesses a thiol-reactive maleimide head group and a triazabutadiene tail group. The maleimide group allows us to robustly ligate to a thiol functionality on a polymer which acts as an anti-biofouling display platform for the glycan-based biorecognition element. Following ligation between the linker molecule and our biorecognition element, we convert the triazabutadiene tail groups into diazonium cations under biocompatible conditions, readily enabling electrografting of the polymer onto carbon electrodes, yielding a ten-fold higher coverage density of the glycan biorecognition element compared to gold–thiol self-assembly (170 pmol cm⁻² compared to 13 pmol cm⁻² using the geometric working electrode surface area) and a commensurate increase in sensitivity to galectin-3, a disease associated biomarker.

Membrane proteins are estimated to be encoded by 30% of eukaryotic and prokaryotic genomes and are key drug targets. A key challenge in the study of membrane proteins is their low solubility in aqueous media, which necessitates the use of detergents. Lipid nanodisc-forming polymers, most commonly styrene maleic acid polymers (SMA), have emerged as powerful tools, allowing extraction, storage, and study of membrane proteins. SMA (and other related polymers) have several shortcomings including unwanted UV absorption and instability to certain metal ions, and there is significant chemical space that has not been explored to optimize their function. This perspective introduces lipid nanodisc-forming polymers and their application and leads into emerging new polymers as alternatives to SMALPS. We also include a summary of key functional assays that can be used to accelerate the discovery of new polymers, particularly focused on assays that are simple to conduct in parallel or in high throughput and require minimal specialist infrastructure.

Macroporous cryogels are formed by polymerising monomers around ice crystal templates, with water as the only waste product making them appealing as tuneable and sustainable scaffolds. Cryogels have found application in diverse areas spanning pollutant removal, vaccine delivery, tissue culture and stationary phases for purification. However, there is an unmet challenge in that the ice crystal templates are intrinsically dynamic and evolve during polymerisation, leading to heterogeneity and complicating reproducibility. Here we overcome this challenge using ice-binding protein-inspired polymers which pre-program the ice crystal template size within cryogels through selective ice crystal surface binding. The ice crystal growth within monomer and ice-binding polymer solutions is first optimized to unlock precision tuning of the resulting pore size. This ice-crystal programming is shown to fine-tune the rheological and mechanical properties of the resulting materials, whilst holding all other parameters constant. The impact of tuneable pore size is demonstrated in model dye removal and release studies. This approach unlocks wider applications of cryogels exploiting biomimetic solutions to tune the crucial ice crystal template.

We demonstrate that engineering the core blocks of nanoparticles derived from polymerization-induced self assembly can tune the ice-recrystallisation inhibition activity: a previously unexplored route to modulate this biomimetic function.

Poly(vinyl alcohol), PVA, is a molar mass-dependent ice recrystallization inhibitor (IRI), with larger polymers that are more active, similar to antifreeze glycoproteins. Attempts to modulate PVA’s IRI activity by side-chain modification or assembly have given limited gains or even a loss of function. Here we take inspiration from antifreeze glycolipids by installing hydrophobic tails at the α-terminus of well-defined PVA derived from RAFT/MADIX photopolymerization, enabled by site-specific capping of the structurally ambiguous ω-end chains. Lower molar mass PVAs (–1) were discovered to have enhanced IRI upon installation of the tails below 0.1 mM, which was more active than small-molecule IRIs of a similar MW. This unlocks new opportunities for IRIs at moderate molar masses and the potential to modulate activity via site-specific end-group chemistry.

Irreversible protein aggregation can cause loss of function of proteins during storage and transport, presenting a challenge in biotherapeutics, biocatalysis, and the food industry, as well as in basic research. New tools to inhibit protein aggregation are required to unlock ambient temperature biologic transportation to reduce the reliance on the cold chain, lower the carbon footprint of biopharmaceutic delivery, and for equitable sharing of medicines. Here we use N-carboxyanhydride polymerization to synthesize block copolymers with short oligo-tryptophan tails to target aggregation-prone regions in proteins, with a hydrophilic and biocompatible poly(sarcosine) solubility block. Poly(sarcosine) is an emerging low toxicity and nonimmunogenic alternative to poly(ethylene glycol), for which immunogenicity is known. Using lysozyme as a fast-aggregating model protein, we show inhibition of aggregation during solution phase agitation challenges by simply mixing the polymer with the protein. Other hydrophobic amino acid blocks were too insoluble to stabilize, and random copolymers had no activity, highlighting the essentiality of the block structure and choice of hydrophobic amino acid residues.