Surface functionalization of exosomes for chondrocyte-targeted siRNA delivery and cartilage regeneration

Hao Zhang; Wenjing Yan; Jinhui Wang; Shuqian Xie; W Andy Tao; Chien-Wei Lee; Xing Zhang; Guiyuan Zhang; Yufeng Liu; Dong Wei; Jing Hu; Haohan Liu; Fengying Liu; Yamei Nie; Xue Chen; Hongtao Xu; Jiang Xia; Shizhi Wang

doi:10.1016/j.jconrel.2024.04.009

Surface functionalization of exosomes for chondrocyte-targeted siRNA delivery and cartilage regeneration

J Control Release. 2024 Apr 6:369:493-505. doi: 10.1016/j.jconrel.2024.04.009. Online ahead of print.

Authors

Hao Zhang¹, Wenjing Yan², Jinhui Wang³, Shuqian Xie², W Andy Tao⁴, Chien-Wei Lee⁵, Xing Zhang², Guiyuan Zhang⁶, Yufeng Liu⁶, Dong Wei⁶, Jing Hu², Haohan Liu², Fengying Liu², Yamei Nie², Xue Chen², Hongtao Xu⁷, Jiang Xia⁸, Shizhi Wang⁹

Affiliations

¹ State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, China; EVLiXiR Biotech Inc., Nanjing 210032, Jiangsu, China.
² Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China.
³ Xiamen Children's Hospital, Xiamen, Fujian, China.
⁴ Departments of Chemistry and Biochemistry, Purdue University, West Lafayette, IN 47907, USA.
⁵ Center for Translational Genomics & Regenerative Medicine Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
⁶ State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
⁷ Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: xhtsmed@gmail.com.
⁸ Department of Chemistry, the Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.. Electronic address: jiangxia@cuhk.edu.hk.
⁹ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China. Electronic address: shizhiwang2009@seu.edu.cn.

PMID: 38582335
DOI: 10.1016/j.jconrel.2024.04.009

Abstract

Osteoarthritis (OA) is the most prevalent degenerative cartilage disease, but no effective treatment is currently available to ameliorate the dysregulation of cartilage catabolism. Cartilage degeneration is closely related to the change in the physiology of chondrocytes: for example, chondrocytes of the OA patients overexpress matrix metallopeptidase 13 (MMP13), a.k.a. collagenase 3, which damages the extracellular matrix (ECM) of the cartilage and deteriorate the disease progression. Inhibiting MMP13 has shown to be beneficial for OA treatments, but delivering therapeutics to the chondrocytes embedded in the dense cartilage is a challenge. Here, we engineered the exosome surface with the cartilage affinity peptide (CAP) through lipid insertion to give chondrocyte-targeting exosomes, CAP-Exo, which was then loaded with siRNA against MMP13 (siMMP13) in the interior to give CAP-Exo/siMMP13. Intra-articular administration of CAP-Exo/siMMP13 reduced the MMP13 level and increased collagen COL2A1 and proteoglycan in cartilage in a rat model of anterior cruciate ligament transection (ACLT)-induced OA. Proteomic analysis showed that CAP-Exo/siMMP13 treatment restored the altered protein levels in the IL-1β-treated chondrocytes. Taken together, a facile exosome engineering method enabled targeted delivery of siRNA to chondrocytes and chondrocyte-specific silencing of MMP13 to attenuate cartilage degeneration.

Keywords: Cartilage regeneration; Chondrocyte targeting; Engineered exosome; Matrix metallopeptidase 13 (MMP13); siRNA.