Conjugation Chemistry Markedly Impacts Toxicity and Biodistribution of Targeted Nanoparticles, Mediated by Complement Activation.

Conjugation chemistries are a major enabling technology for the development of drug delivery systems, from antibody-drug conjugates to antibody-targeted lipid nanoparticles inspired by the success of the COVID-19 vaccine. However, here it is shown that for antibody-targeted nanoparticles, the most popular conjugation chemistries directly participate in the activation of the complement cascade of plasma proteins. Their activation of complement leads to large changes in the biodistribution of nanoparticles (up to 140-fold increased uptake into phagocytes of the lungs) and multiple toxicities, including a 50% drop in platelet count.

Multi-stage-mixing to create a core-then-shell structure improves DNA-loaded lipid nanoparticles' transfection by orders of magnitude.

The unprecedented success of mRNA-lipid nanoparticles (LNPs) has highlighted their power for protein expression, but the hours-long half-life of mRNA severely limits their use in chronic diseases. In contrast, DNA LNPs display months-long expression and genetically encode cell type specificity, but their use has been hindered by poor protein expression (orders of magnitude lower than mRNA LNPs). To overcome this, we introduce multi-stage mixing (MSM) microfluidics to control the internal structure of LNPs and use it to create core-then-shell (CTS) structured DNA LNPs.

A percolation-type criticality threshold controls immune protein coating of surfaces.

When a material enters the body, it is immediately attacked by hundreds of proteins, organized into complex networks of binding interactions and reactions. How do such complex systems interact with a material, "deciding" whether to attack? We focus on the "complement" system of ∼40 blood proteins that bind microbes, nanoparticles, and medical devices, initiating inflammation. We show a sharp threshold for complement activation upon varying a fundamental material parameter, the surface density of potential complement attachment points.

Delayed monetary losses: Do different procedures and discounting measures assess the same construct?

The present study examined two procedures for assessing the discounting of delayed, hypothetical, monetary losses: the Adjusting-Amount procedure (Estle et al., 2006) and the Delayed Losses Questionnaire (Myerson et al., 2017), which was modeled on Kirby et al.

Marginated Neutrophils in the Lungs Effectively Compete for Nanoparticles Targeted to the Endothelium, Serving as a Part of the Reticuloendothelial System.

Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but has yet to achieve this goal with the vast majority of targets. One rare example of success in this pursuit has been the 25+ years of studies targeting the lung endothelium using nanoparticles conjugated to antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target the lungs' numerous marginated neutrophils, which reside in the pulmonary capillaries and patrol for pathogens.