Small extracellular vesicles in combination with sleep-related circRNA3503: A targeted therapeutic agent with injectable thermosensitive hydrogel to prevent osteoarthritis

Shi-Cong Tao; Ji-Yan Huang; Yuan Gao; Zi-Xiang Li; Zhan-Ying Wei; Helen Dawes; Shang-Chun Guo

doi:10.1016/j.bioactmat.2021.04.031

Small extracellular vesicles in combination with sleep-related circRNA3503: A targeted therapeutic agent with injectable thermosensitive hydrogel to prevent osteoarthritis

Bioact Mater. 2021 May 6;6(12):4455-4469. doi: 10.1016/j.bioactmat.2021.04.031. eCollection 2021 Dec.

Authors

Shi-Cong Tao¹, Ji-Yan Huang², Yuan Gao³, Zi-Xiang Li⁴, Zhan-Ying Wei⁵, Helen Dawes⁶, Shang-Chun Guo^{1

7}

Affiliations

¹ Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
² Department of Stomatology, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 185 Pu'an Road, Shanghai, 200021, China.
³ School of Medicine, Shanghai Jiao Tong University, 227 South Chongqing Road, Shanghai, 200025, China.
⁴ Medical College of Soochow University, Soochow University, Changzhou, 215123, Jiangsu, China.
⁵ Shanghai Clinical Research Centre of Bone Diseases, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
⁶ Faculty of Health and Life Science, Oxford Brookes University, Headington Road, Oxford, OX3 0BP, UK.
⁷ Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.

Abstract

Osteoarthritis (OA), characterized by chondrocyte apoptosis and disturbance of the balance between catabolism and anabolism of the extracellular matrix (ECM), is the most common age-related degenerative joint disease worldwide. As sleep has been found to be beneficial for cartilage repair, and circular RNAs (circRNAs) have been demonstrated to be involved in the pathogenesis of OA, we performed RNA sequencing (RNA-seq), and found circRNA3503 was significantly increased after melatonin (MT)-induced cell sleep. Upregulation of circRNA3503 expression completely rescued the effects of interleukin-1β (IL-1β), which was used to simulate OA, on apoptosis, ECM degradation- and synthesis-related genes. Mechanistically, circRNA3503 acted as a sponge of hsa-miR-181c-3p and hsa-let-7b-3p. Moreover, as we previously showed that small extracellular vesicles (sEVs) derived from synovium mesenchymal stem cells (SMSCs) can not only successfully deliver nucleic acids to chondrocytes, but also effectively promote chondrocyte proliferation and migration, we assessed the feasibility of sEVs in combination with sleep-related circRNA3503 as an OA therapy. We successfully produced and isolated circRNA3503-loaded sEVs (circRNA3503-OE-sEVs) from SMSCs. Then, poly(D,l-lactide)-b-poly(ethylene glycol)-b-poly(D,l-lactide) (PDLLA-PEG-PDLLA, PLEL) triblock copolymer gels were used as carriers of sEVs. Through in vivo and in vitro experiments, PLEL@circRNA3503-OE-sEVs were shown to be a highly-effective therapeutic strategy to prevent OA progression. Through multiple pathways, circRNA3503-OE-sEVs alleviated inflammation-induced apoptosis and the imbalance between ECM synthesis and ECM degradation by acting as a sponge of hsa-miR-181c-3p and hsa-let-7b-3p. In addition, circRNA3503-OE-sEVs promoted chondrocyte renewal to alleviate the progressive loss of chondrocytes. Our results highlight the potential of PLEL@circRNA3503-OE-sEVs for preventing OA progression.

Keywords: Circular RNAs; Exosomes; Extracellular vesicles; Osteoarthritis; PDLLA-PEG-PDLLA.