Exosome-Inspired Lipid Nanoparticles for Enhanced Tissue Penetration

The extracellular matrix (ECM) is a complex network of biomolecules with varying pore sizes, posing a challenge for the effective penetration of lipid nanoparticles. In contrast, cell-derived lipid nanoparticles, such as exosomes, have demonstrated the ability to travel to distant organs, indicating their capacity to penetrate the ECM. Here, we designed exosome-like vesicles (ELVs) inspired by exosomes' distinct transport phenomena. Specifically, we integrated three exosomal components (anionic lipid, cholesterol, and aquaporin-1) associated with transport into our ELVs to mimic the superior diffusion behavior of exosomes over synthetic lipid nanoparticles. Surprisingly, both bulk- and single-particle-diffusion studies revealed a more than 33 times increase in the effective diffusion coefficient within model ECM compared to conventional lipid nanoparticles. Furthermore, ELVs show an 80% increase in the effective diffusion coefficient within biological tissues. The excellent transport behavior of ELVs was further validated in vivo, where intratumoral injection showcased their superior transport. These findings provide insights into lipid nanoparticle design for improved tissue penetration.