The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer-TLR-7/8a) and evaluated how varying physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer-TLR-7/8a was critical for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular platform in which protein antigens are site-specifically linked to temperature-responsive polymer-TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.

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Agonists of immune cell receptors direct innate and adaptive immunity. These agonists range in size and complexity from small molecules to large macromolecules. Here, agonists of a class of immune cell receptors known as the Toll-Like Receptors (TLRs) are highlighted focusing on the distinctive molecular moieties that pertain to receptor binding and activation. How the structure and combined chemical signals translate into a variety of immune responses remain major questions in the field. In this structure-focused review, we outline potential areas where the tools of chemical biology could help decipher the emerging molecular codes that direct immune stimulation.

State-of-the art photoactivation strategies in chemical biology provide spatiotemporal control and visualization of biological processes. However, using high energy light (l < 500 nm) for substrate or photocatalyst sensitization can lead to background activation of photoactive small molecule probes and reduce its efficacy in complex biological environments. Here we describe the development of targeted aryl azide activation via deep red light (l = 660 nm) photoredox catalysis and its use in photocatalyzed proximity labeling. We demonstrate that aryl azides are converted to triplet nitrenes via a novel redox-centric mechanism and show that its spatially localized-formation requires both red light and a photocatalyst-targeting modality. This technology was applied in different colon cancer cell systems for targeted protein environment labeling of epithelial cell adhesion molecule (EpCAM). We identified a small subset of proteins with previously known and unknown association to EpCAM, including CDH3, a clinically relevant protein that shares high tumor selective expression with EpCAM.

Metal fluorides (MF) are one of the most attractive cathode candidates for Li ion batteries (LIBs) due to their high conversion potentials with large capacities. However, only a limited number of synthetic methods, generally involving highly toxic or inaccessible reagents, currently exist, which has made it difficult to produce well-designed nanostructures suitable for cathodes; consequently, harnessing their potential cathodic properties has been a challenge. Herein, we report a new bottom-up synthetic method utilizing ammonium fluoride (NHF) for the preparation of anhydrous MF (CuF, FeF, and CoF)/mesoporous carbon (MSU-F-C) nanocomposites, whereby a series of metal precursor nanoparticles preconfined in mesoporous carbon were readily converted to anhydrous MF through simple heat treatment with NHF under solventless conditions. We demonstrate the versatility, lower toxicity, and efficiency of this synthetic method and, using XRD analysis, propose a mechanism for the reaction. All MF/MSU-F-C prepared in this study exhibited superior electrochemical performances, through conversion reactions, as the cathode for LIBs. In particular, FeF/MSU-F-C maintained a capacity of 650 mAh g across 50 cycles, which is ∼90% of its initial capacity. We expect that this facile synthesis method will trigger further research into the development of various nanostructured MF for use in energy storage and other applications.