ABSTRACT Despite the growing importance of lipid nanoparticles (LNPs) in mRNA therapeutics, current ionizable lipids, which comprise an ionizable head group, a linker, and hydrophobic tails that collectively govern the delivery behavior, exhibit dose‐limiting toxicity and suboptimal efficiency. Hydrophobic tail chemistry has been implicated in these limitations; however, a systematic structure–activity relationship (SAR) analysis is lacking. In this study, the authors synthesized a 56‐member library of tail‐modified ionizable lipids with biodegradable disulfide linkages and variations in chain length and branching. Systematic SAR evaluation revealed that hydrophobic tail architecture critically determines endosomal escape, biocompatibility, and mRNA translation efficiency. Optimized LNPs delivered mRNA with potent efficacy and markedly reduced cytotoxicity, lower cytokine induction, and balanced Th1/Th2 immune activation in a nonhuman primate model. The findings establish the first comprehensive SAR framework linking tail chemistry to ionizable lipid function, offering molecular design principles for next‐generation LNPs and enabling the development of safer and more effective mRNA‐based vaccines and therapeutics.
Seo-Hyeon Bae, Jisun Lee, J. Ahn et al.· Advancement of science· 0 citations
Influenza D virus (IDV) is an emerging orthomyxovirus with cattle as its principal reservoir, and D/Yama2019‐lineage viruses have become dominant in East Asia. Although IDV has been detected in Korean cattle, the genomic identity, phylogenetic placement, and regional evolutionary relationships of circulating Korean strains have not been defined. To address these gaps, nasal swabs were collected from 578 cattle with mild respiratory signs on 157 farms across eight provinces in South Korea during 2022–2023 and screened by RT‐qPCR targeting the PB1 gene. Positive samples underwent complete genome sequencing of all seven segments, followed by maximum‐likelihood and Bayesian phylogenetic analyses, discrete phylogeographic inference using a Bayesian stochastic search variable selection (BSSVS) model, and positive selection analyses. Six samples from three farms were IDV‐positive (sample‐level positivity: 1.04%; farm‐level positivity: 1.9%), all from 8‐to‐10‐month‐old calves. Phylogenetic analysis of all seven genomic segments placed all six Korean strains within the D/Yama2019 lineage with strong bootstrap support (99%–100%), forming a monophyletic cluster more closely related to Chinese than to Japanese D/Yama2019 reference strains. No phylogenetic evidence of reassortment was detected. Bayesian time‐scaled analysis estimated the most recent common ancestor of the Korean strains at ~2018.1–2020.1 across all seven segments. HEF‐based BSSVS analysis suggested a China‐to‐South Korea transition within the sampled dataset (posterior probability (PP) = 0.982; Bayes factor (BF) = 163.67), although this result should be interpreted in light of the small number of Korean sequences and the single‐segment basis of the phylogeographic analysis. Positive selection analyses revealed limited, method‐dependent signals without support from the fixed effects likelihood model, and Korean‐associated amino acid substitutions in PB1, P3, NS1, and NS2 were interpreted as lineage‐associated molecular signatures rather than evidence of adaptive evolution. These findings provide a whole‐genome baseline for IDV surveillance in South Korea and support continued longitudinal monitoring to clarify the persistence and transmission dynamics of D/Yama2019‐lineage viruses in the region.
Byunghyun An, Kyungmoon Lee, Hai-Quynh Do et al.· Transboundary and Emerging D...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
