Exosome-based biomimetic nanoparticles targeted to inflamed joints for enhanced treatment of rheumatoid arthritis

Abstract

Background: Glucocorticoids (GCs) show powerful treatment effect on rheumatoid arthritis (RA). However, the clinical application is limited by their nonspecific distribution after systemic administration, serious adverse reactions during long-term administration. To achieve better treatment, reduce side effect, we here established a biomimetic exosome (Exo) encapsulating dexamethasone sodium phosphate (Dex) nanoparticle (Exo/Dex), whose surface was modified with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) compound to attain FPC-Exo/Dex active targeting drug delivery system. Results: The size of FPC-Exo/Dex was 128.43 ± 16.27 nm, with a polydispersity index (PDI) of 0.36 ± 0.05, and the Zeta potential was − 22.73 ± 0.91 mV. The encapsulation efficiency (EE) of the preparation was 10.26 ± 0.73%, with drug loading efficiency (DLE) of 18.81 ± 2.05%. In vitro study showed this system displayed enhanced endocytosis and excellent anti-inflammation effect against RAW264.7 cells by suppressing pro-inflammatory cytokines and increasing anti-inflammatory cytokine. Further biodistribution study showed the fluorescence intensity of FPC-Exo/Dex was stronger than other Dex formulations in joints, suggesting its enhanced accumulation to inflammation sites. In vivo biodistribution experiment displayed FPC-Exo/Dex could preserve the bone and cartilage of CIA mice better and significantly reduce inflamed joints. Next in vivo safety evaluation demonstrated this biomimetic drug delivery system had no obvious hepatotoxicity and exhibited desirable biocompatibility. Conclusion: The present study provides a promising strategy for using exosome as nanocarrier to enhance the therapeutic effect of GCs against RA.

Therapeutic Application of Exosomes in Inflammatory Diseases

“…Exosomes loaded with dexamethasone exhibited anti-inflammatory effects in RAW264.7 cells in vitro. The exosomes preserved bone and cartilage, and reduced joint inflammation in a collagen induced arthritis (CIA) mouse model [ 63 ]. Doxorubicin encapsulated exosomes derived from mouse immature dendritic cells reduced breast cancer cell viability in vitro and inhibited tumor growth in a tumor-bearing nude mouse model without toxicity [ 64 ].…”

Application of nanomaterials in the treatment of rheumatoid arthritis

“…66 Nanoparticle drug delivery based on exosomes has been successfully applied to a variety of different diseases, such as cancer, Parkinson, nephropathy and encephalitis, [67][68][69][70] but so far is rarely used for RA. Yan et al 71 synthesized a biomimetic exosome (Exo) encapsulated with dexamethasone sodium phosphate (Dex) nanoparticles (Exo/ Dex), which was modied with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) complex (FPC-Exo/Dex) to target inammatory joints. The uptake of RAW264.7 cells with the nanoparticle and further biological distribution studies showed that FPC-Exo/Dex could aggregate at the site of inammation.…”

Expedition into Exosome Biology: A Perspective of Progress from Discovery to Therapeutic Development

“…The expression of targeting peptides or proteins on exosome surface is a prerequisite for the specific delivery of therapeutic cargoes and in avoiding the adverse effects associated with chemotherapeutic agents on normal cells surrounding tumors. Although many studies have been performed on the exosome-based delivery of therapeutic cargoes, few have addressed the engineering of exosomes to achieve the target-specific delivery of therapeutic cargoes [ 240 , 241 , 242 , 243 , 244 ]. The exosome-engineering aimed at inserting a peptide correctly into exosomes, while avoiding cleavage of peptide regions, is accomplished by expressing the target peptide as a fusion product with the surface localized lysosomal associated membrane protein-2b (Lamp-2b) [ 245 , 246 ].…”