No abstract

Arraying antigens in a multivalent nanoparticle form is often employed in vaccine design, but in vivo mechanisms underlying the enhanced immunity elicited by such vaccines remain poorly understood. Here we studied the fate of two different heavily glycosylated HIV antigens in protein nanoparticle or “free” forms following primary immunization. Unlike monomeric antigens, nanoparticles were rapidly shuttled to the follicular dendritic cell (FDC) network followed by concentration in germinal centers, in a complement-, mannose-binding lectin (MBL)-, and immunogen glycan-dependent manner. Loss of FDC localization in MBL-deficient mice or via immunogen deglycosylation significantly impacted antibody responses. These findings identify a novel innate immune-mediated recognition pathway promoting humoral immunity to particulate antigens, with broad implications for humoral immunity to microbes and the design of improved vaccines.

Chiral poly-amido-saccharides (PASs) with a defined molecular weight and narrow polydispersity are synthesized using an anionic ring-opening polymerization of a β-lactam sugar monomer. The PASs have a previously unreported main chain structure that is composed of pyranose rings linked through the 1- and 2-positions by an amide bond with α-stereochemistry. The monomer is synthesized in one-step from benzyl-protected d-glucal and polymerized using mild reaction conditions to give degrees of polymerization ranging from 25 to >150 in high yield. Computational modeling reveals how the monomer’s structure and steric bulk affect the thermodynamics and kinetics of polymerization. Protected and deprotected polymers and model compounds are characterized using a variety of methods (NMR, GPC, IR, DLS, etc.). Reductive debenzylation provides the deprotected, hydrophilic polymers in high yield. Based on circular dichroism, the deprotected polymers possess a regular secondary structure in aqueous solution, which agrees favorably with the prediction of a helical structure using molecular modeling. Furthermore, we provide evidence suggesting that the polymers bind the lectin concanavalin A at the same site as natural carbohydrates, showing the potential of these polymers to mimic natural polysaccharides. PASs offer the advantages associated with synthetic polymers, such as greater control over structure and derivitization, and less batch-to-batch variation. At the same time, they preserve many of the structural features of natural polysaccharides, such as a stereochemically regular, rigid pyranose backbone, that make natural carbohydrate polymers important materials both for their unique properties and useful applications.

The emergence and re-emergence of bacterial strains that are resistant to current antibiotics reveals the clinical need for new agents that possess broad-spectrum antibacterial activity. Furthermore, bacteriophobic coatings that repel bacteria are important for medical devices, as the lifetime, reliability, and performance of implant devices are hindered by bacterial adhesion and infection. Dendrimers, a specific class of monodisperse macromolecules, have recently shown potential to function as both antibacterial agents as well as antimicrobial surface coatings. This review discusses the limitations with currently used antibacterial agents and describes how various classes of dendrimers, including glycodendrimers, cationic dendrimers, anionic dendrimers, and peptide dendrimers, have the potential to improve upon or replace certain antibiotics. Furthermore, the unexplored areas in this field of research will be mentioned to present opportunities for additional studies regarding the use of dendrimers as antimicrobial agents.

Activation of the innate immune STimulator of INterferon Genes (STING) pathway potentiates antitumour immunity, but systemic delivery of STING agonists to tumours is challenging. We conjugated STING-activating cyclic dinucleotides (CDNs) to PEGylated lipids (CDN-PEG-lipids; PEG, polyethylene glycol) via a cleavable linker and incorporated them into lipid nanodiscs (LNDs), which are discoid nanoparticles formed by self-assembly. Compared to state-of-the-art liposomes, intravenously administered LNDs carrying CDN-PEG-lipid (LND-CDNs) exhibited more efficient penetration of tumours, exposing the majority of tumour cells to STING agonist. A single dose of LND-CDNs induced rejection of established tumours, coincident with immune memory against tumour rechallenge. Although CDNs were not directly tumoricidal, LND-CDN uptake by cancer cells correlated with robust T-cell activation by promoting CDN and tumour antigen co-localization in dendritic cells. LNDs thus appear promising as a vehicle for robust delivery of compounds throughout solid tumours, which can be exploited for enhanced immunotherapy.