Chemical Modulation of Bioengineered Exosomes for Tissue‐Specific Biodistribution

Abstract The physicochemical properties of nanomaterials play a key role in tissue‐specific targeting by reducing nonspecific background uptake as well as controlling biodistribution and clearance. Due to the strong influence of surface chemistry, chemical modulation of bioinert exosomes with chargeable and traceable small molecule fluorophores has a significant effect on the targeting, stability, and toxicity of the final conjugates. In this study, charge‐variable exosomes are designed by conjugating their surface proteins with near‐infrared fluorophores to control the in vivo fate of exosomes. Interestingly, zwitterionic fluorophore‐labeled exosomes show rapid renal clearance with minimum to none nonspecific tissue uptake, whereas anionic exosomes are excreted through the hepatobiliary route with high uptake in the liver. The biodistribution and pharmacokinetics of exosome conjugates are comparable to their corresponding free fluorophores, demonstrating that the surface characteristics govern the fate of final conjugates in the living organism. Such unique surface properties of chemically modulated exosomes are confirmed in the lymphatic system after intradermal administration, which results in distinctive kinetic profiles in the secondary lymphoid tissues. This finding can subsequently serve as the foundation for developing tissue‐specific exosome‐based therapeutics.