Discovery of a Peptoid-Based Nanoparticle Platform for Therapeutic mRNA Delivery via Diverse Library Clustering and Structural Parametrization.

Nanoparticle-mediated mRNA delivery has emerged as a promising therapeutic modality, but its growth is still limited by the discovery and optimization of effective and well-tolerated delivery strategies. Lipid nanoparticles containing charged or ionizable lipids are an emerging standard for in vivo mRNA delivery, so creating facile, tunable strategies to synthesize these key lipid-like molecules is essential to advance the field. Here, we generate a library of N-substituted glycine oligomers, peptoids, and undertake a multistage down-selection process to identify lead candidate peptoids as the ionizable component in our Nutshell nanoparticle platform.

Tunable Intervalence Charge Transfer in Ruthenium Prussian Blue Analog Enables Stable and Efficient Biocompatible Artificial Synapses.

Emerging concepts for neuromorphic computing, bioelectronics, and brain-computer interfacing inspire new research avenues aimed at understanding the relationship between oxidation state and conductivity in unexplored materials. This report expands the materials playground for neuromorphic devices to include a mixed valence inorganic 3D coordination framework, a ruthenium Prussian blue analog (RuPBA), for flexible and biocompatible artificial synapses that reversibly switch conductance by more than four orders of magnitude based on electrochemically tunable oxidation state. The electrochemically tunable degree of mixed valency and electronic coupling between N-coordinated Ru sites controls the carrier concentration and mobility, as supported by density functional theory computations and application of electron transfer theory to in situ spectroscopy of intervalence charge transfer.

Modulating the Influenza A Virus-Target Membrane Fusion Interface With Synthetic DNA-Lipid Receptors.

Influenza A virus (IAV) binds to sialylated glycans on the cell membrane before endocytosis and fusion. Cell-surface glycans are highly heterogeneous in length and glycosylation density, which leads to variations in the distance and rigidity with which IAV is held away from the cell membrane. To gain mechanistic insight into how receptor length and rigidity impact the mechanism of IAV entry, we employed synthetic DNA-lipids as highly tunable surrogate receptors.

Membrane-tethered mucin-like polypeptides sterically inhibit binding and slow fusion kinetics of influenza A virus.

The mechanism(s) by which cell-tethered mucins modulate infection by influenza A viruses (IAVs) remain an open question. Mucins form both a protective barrier that can block virus binding and recruit IAVs to bind cells via the sialic acids of cell-tethered mucins. To elucidate the molecular role of mucins in flu pathogenesis, we constructed a synthetic glycocalyx to investigate membrane-tethered mucins in the context of IAV binding and fusion.

pH Dependence of Zika Membrane Fusion Kinetics Reveals an Off-Pathway State.

The recent spread of Zika virus stimulated extensive research on its structure, pathogenesis, and immunology, but mechanistic study of entry has lagged behind, in part due to the lack of a defined reconstituted system. Here, we report Zika membrane fusion measured using a platform that bypasses these barriers, enabling observation of single-virus fusion kinetics without receptor reconstitution. Surprisingly, target membrane binding and low pH are sufficient to trigger viral hemifusion to liposomes containing only neutral lipids.

Low-Temperature Adsorption and Diffusion of Methanol in ZIF-8 Nanoparticle Films.

The adsorption of methanol by a zeolitic imidazolate framework-8 (ZIF-8) nanoparticle thin film was studied in situ using temperature-programmed desorption and X-ray photoelectron spectroscopy under low-temperature, low-pressure conditions. Partial pore penetration was observed at 90 K, but upon increasing the exposure temperature of the film to 130 K pore penetration was significantly enhanced. Although many studies exist involving bulk powders, this is the first work to our knowledge that demonstrates the ability to control and monitor the entry of a molecule into a metal organic framework (MOF) film in situ using temperature.

Investigating the proteome reactivity and selectivity of aryl halides.

Protein-reactive electrophiles are critical to chemical proteomic applications including activity-based protein profiling, site-selective protein modification, and covalent inhibitor development. Here, we explore the protein reactivity of a panel of aryl halides that function through a nucleophilic aromatic substitution (S(N)Ar) mechanism. We show that the reactivity of these electrophiles can be finely tuned by varying the substituents on the aryl ring.