Exosomes as Drug Delivery Systems: Endogenous Nanovehicles for Treatment of Systemic Lupus Erythematosus

Abstract

Exosomes, nanometer-sized lipid-bilayer-enclosed extracellular vesicles (EVs), have attracted increasing attention due to their inherent ability to shuttle proteins, lipids and genes between cells and their natural affinity to target cells. Their intrinsic features such as stability, biocompatibility, low immunogenicity and ability to overcome biological barriers, have prompted interest in using exosomes as drug delivery vehicles, especially for gene therapy. Evidence indicates that exosomes play roles in both immune stimulation and tolerance, regulating immune signaling and inflammation. To date, exosome-based nanocarriers delivering small molecule drugs have been developed to treat many prevalent autoimmune diseases. This review highlights the key features of exosomes as drug delivery vehicles, such as therapeutic cargo, use of targeting peptide, loading method and administration route with a broad focus. In addition, we outline the current state of evidence in the field of exosome-based drug delivery systems in systemic lupus erythematosus (SLE), evaluating exosomes derived from various cell types and engineered exosomes.

Keywords: autoimmunity; drug delivery; exosomes; extracellular vesicles; microparticles; systemic lupus erythematosus; therapy.

Figure 1

Biogenesis, secretion, uptake and molecular composition of exosomes. (A) exosomes from intraluminal vesicles (ILVs) in multivesicular bodies (MVBs) are secreted extracellularly by fusion with the cellular membrane. Next, exosomes interacting with recipient cells directly by surface binding, membrane fusion or internalization will target exogenous exosomes in the canonical endosomal pathway by lipid raft, clathrin, caveloae or micropinocytosis/phagocytosis processes. (B) exosomes can contain different types of cell surface proteins (tetraspanins, integrins, major histocompatibility complex (MHC), etc.), intracellular protein (skeletal proteins, heat shock proteins, etc.), nucleic acids (RNA, DNA, microRNAs (miRNA), long non-coding RNA (lncRNA), etc.), amino acids, lipids and metabolites. They are mediators of near and long-distance intercellular communication in health and disease, affecting several aspects of cell biology. This, together with their intrinsic features such as stability, biocompatibility, low immunogenicity and ability to overcome biological barriers, has prompted interest in using exosomes as drug delivery vehicles.

Figure 2

Schematic illustration of the key points in exosomes as drug delivery systems. Therapeutic cargos, methods for loading exosomes with these cargos, the use of targeting peptides on the exosome surface and routes of administration to reach the area of interest, are important issues that still need to be deeply addressed.

Figure 3

Natural exosomes and engineered exosomes loaded with endogenous or exogenous cargos for therapeutic purposes. Immune-therapeutic exosomes include naturally occurring exosomes mainly from mesenchymal stem cells (route 1); exosomes secreted by modified cells due to pathological factors or transfection (route 2); and exosomes loaded with exogenous cargos classified into three kinds, mainly including small molecule drugs, such as curcumin and glucocorticoids (GC), nucleic acids (miRNA, small interference RNA (siRNA), lncRNA, etc.), proteins and peptides (route 3). These exosomes can be surface-modified with targeting peptides for a successful exosome-based drug delivery system. In the context of systemic lupus erythematosus, immunosuppression, cartilage repair and renoprotection are important pathways regulated in target cells by exosome-based drug delivery. shRNA: Small hairpin RNA.

Figure 4

Clinical manufacturing approaches to produce exosome-based therapeutics. Large-scale good manufacturing practice (GMP)-exosome production under GMP-compliant procedures to ensure the quality, safety and consistency. EVs: Extracellular vesicles.