Biodistribution of Exosomes and Engineering Strategies for Targeted Delivery of Therapeutic Exosomes

Abstract

Exosomes are cell-secreted nano-sized vesicles which deliver diverse biological molecules for intercellular communication. Due to their therapeutic potential, exosomes have been engineered in numerous ways for efficient delivery of active pharmaceutical ingredients to various target organs, tissues, and cells. In vivo administered exosomes are normally delivered to the liver, spleen, kidney, lung, and gastrointestinal tract and show rapid clearance from the blood circulation after systemic injection. The biodistribution and pharmacokinetics (PK) of exosomes can be modulated by engineering various factors such as cellular origin and membrane protein composition of exosomes. Recent advances accentuate the potential of targeted delivery of engineered exosomes even to the most challenging organs including the central nervous system. Major breakthroughs have been made related to various imaging techniques for monitoring in vivo biodistribution and PK of exosomes, as well as exosomal surface engineering technologies for inducing targetability. For inducing targeted delivery, therapeutic exosomes can be engineered to express various targeting moieties via direct modification methods such as chemically modifying exosomal surfaces with covalent/non-covalent bonds, or via indirect modification methods by genetically engineering exosome-producing cells. In this review, we describe the current knowledge of biodistribution and PK of exosomes, factors determining the targetability and organotropism of exosomes, and imaging technologies to monitor in vivo administered exosomes. In addition, we highlight recent advances in strategies for inducing targeted delivery of exosomes to specific organs and cells.

Keywords: Biodistribution; Exosome; Pharmacokinetics; Targeted delivery.

Fig. 1

Targeting and biodistribution/PK analysis strategies of exosome therapeutics. Targeting of exosomes to specific organs or cells could be achieved via modification of the composition of exosomal membrane proteins including tetraspanins and integrins. Exosomal surface engineering by displaying targeting peptides conjugated with exosomal membrane-associated domains such as lysosome-associated membrane glycoprotein 2b (Lamp2b) or C1C2 domain of lactadherin (LA) is another approach for active tissue targeting. Both glycan and lipid compositions of exosomal membrane also contribute to the biodistribution of administered exosomes. Biodistribution/PK analysis of administered exosomes can be conducted via various exosome labeling methods (i.e., bioluminescence, fluorescence, and radio isotope-labeling methods)

Fig. 2

Schematic of genetic modification strategies for active targeting of exosomes. The vectors are designed to express the targeting moieties conjugated with exosomal membrane localizing domains, with the representative applications shown as follows: Tetraspanins, glycosylphosphatidylinositol (GPI), lysosomal-associated membrane protein 2 (Lamp2b), and C1C2 domain of LA. Cell/tissue-targeting peptides, receptors, and antibodies (scFv and nanobodies) are candidates of targeting moieties for specific tissue delivery. After the vectors are transfected into exosome-producing cells, the cells release the exosomes expressing targeting moieties on their surface