Modular Assembly of Lipid Nanoparticles for Targeted mRNA Therapeutics and Vaccines

Abstract Targeted mRNA delivery remains a key challenge for lipid nanoparticles (LNPs), as existing surface functionalization strategies often suffer from uncontrolled cross‐linking, aggregation, and immunogenicity. Conventional tetrameric streptavidin‐biotin coupling, while biochemically robust, has limited translational potential due to its multivalency and poor structural control. Here, a monomeric streptavidin (mSA)‐based modular assembly platform is presented that enables rapid, stable, and customizable functionalization of LNPs. The monovalent design of mSA prevents aggregation and significantly reduces immunogenicity compared with conventional streptavidin. By fusing mSA to Fc‐binding domains (Z and C), universal linkers are created that can directly bind unmodified commercial antibodies, allowing plug‐and‐play construction of targeted LNPs without chemical modification. This approach supports interchangeable antigen or antibody labeling, yielding monodisperse and reproducible nanoparticles. Demonstrated across diverse therapeutic contexts—including virus‐like nanoparticle vaccines, tumor‐targeted mRNA therapy, and efficient transfection of primary mouse T cells (up to 98%)—the platform offers a generalizable and clinically adaptable strategy for precise mRNA delivery and vaccine development.