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

ABSTRACT: 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. It is founded that the mechanism of complement activation varies dramatically between different conjugation chemistries. Dibenzocyclooctyne, a commonly used click

SUBMITTER: Zaleski MH 

PROVIDER: S-EPMC11795710 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature