Polyphenolic Nanoparticle Platforms (PARCELs) for In Vitro and In Vivo mRNA Delivery.

Despite their successful implementation in the COVID-19 vaccines, lipid nanoparticles (LNPs) still face a central limitation in the delivery of mRNA payloads: endosomal trapping. Improving upon this inefficiency could afford improved drug delivery systems, paving the way toward safer and more effective mRNA-based medicines. Here, we present polyphenolic nanoparticle platforms (PARCELs) as effective mRNA delivery systems. In brief, our investigation begins with a computationally guided structural analysis of 1825 discrete polyphenolic structural data points across 73 diverse small molecule polyphenols and 25 molecular parameters. We then generate structurally diverse PARCELs, evaluating their in vitro mechanism and activity, ultimately highlighting the superior endosomal escape properties of PARCELs relative to analogous LNPs. Finally, we examine the in vivo biodistribution, protein expression, and therapeutic efficacy of PARCELs in mice. In undertaking this approach, the goal of this study is to establish PARCELs as viable delivery platforms for safe and effective mRNA delivery.

Single-tailed heterocyclic carboxamide lipids for macrophage immune-modulation.

The discovery of new immune-modulating biomaterials is of significant value to immuno-engineering and therapy development. Here, we discovered that single-tailed heterocyclic carboxamide lipids preferentially modulated macrophages - but not dendritic cells - by interfering with sphingosine-1-phosphate-related pathways, consequently increasing interferon alpha expression. We further performed extensive downstream correlation analysis and determined key factors in physicochemical properties likely to modulate pro-inflammatory and anti-inflammatory immune responses. These properties will be useful for the rational design of the next generation of cell type-specific immune-modulating lipids.