DNA-Directed Assembly of Multivalent Lipid Nanoparticles for Targeted T Cell Gene Delivery

A major challenge in in vivo gene delivery is achieving both precise targeting and efficient mRNA translation. Multitargeted LNPs offer a potential solution to this challenge; however, their rapid assembly remains difficult, necessitating the development of new methods to construct and evaluate targeted LNPs. Here, we use a DNA-tethering method to enable rapid antibody modification of LNPs and evaluate bispecific formulations for targeted T cell mRNA delivery in vitro and in vivo . We find bispecific LNPs improve T cell targeting and expression compared to single-targeted particles. To the best of our knowledge, this study represents the first systematic screening and comparison of bispecific LNPs. Our method provides a modular approach for identifying effective antibody combinations to enhance in vivo gene delivery that can be customized for different undruggable diseases.