Mitochondrial-Oriented Injectable Hydrogel Microspheres Maintain Homeostasis of Chondrocyte Metabolism to Promote Subcellular Therapy in Osteoarthritis

Li Chen; Jianye Yang; Zhengwei Cai; Yanran Huang; Pengcheng Xiao; Hong Chen; Xiaoji Luo; Wei Huang; Wenguo Cui; Ning Hu

doi:10.34133/research.0306

Mitochondrial-Oriented Injectable Hydrogel Microspheres Maintain Homeostasis of Chondrocyte Metabolism to Promote Subcellular Therapy in Osteoarthritis

Research (Wash D C). 2024 Jan 25:7:0306. doi: 10.34133/research.0306. eCollection 2024.

Authors

Li Chen¹, Jianye Yang^{1

2}, Zhengwei Cai², Yanran Huang^{1

2}, Pengcheng Xiao^{1

2}, Hong Chen¹, Xiaoji Luo¹, Wei Huang¹, Wenguo Cui², Ning Hu¹

Affiliations

¹ Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Orthopedic Laboratory of Chongqing Medical University, Chongqing 400016, China.
² Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China.

Abstract

Subcellular mitochondria serve as sensors for energy metabolism and redox balance, and the dynamic regulation of functional and dysfunctional mitochondria plays a crucial role in determining cells' fate. Selective removal of dysfunctional mitochondria at the subcellular level can provide chondrocytes with energy to prevent degeneration, thereby treating osteoarthritis. Herein, to achieve an ideal subcellular therapy, cartilage affinity peptide (WYRGRL)-decorated liposomes loaded with mitophagy activator (urolithin A) were integrated into hyaluronic acid methacrylate hydrogel microspheres through microfluidic technology, named HM@WY-Lip/UA, that could efficiently target chondrocytes and selectively remove subcellular dysfunctional mitochondria. As a result, this system demonstrated an advantage in mitochondria function restoration, reactive oxygen species scavenging, cell survival rescue, and chondrocyte homeostasis maintenance through increasing mitophagy. In a rat post-traumatic osteoarthritis model, the intra-articular injection of HM@WY-Lip/UA ameliorated cartilage matrix degradation, osteophyte formation, and subchondral bone sclerosis at 8 weeks. Overall, this study indicated that HM@WY-Lip/UA provided a protective effect on cartilage degeneration in an efficacious and clinically relevant manner, and a mitochondrial-oriented strategy has great potential in the subcellular therapy of osteoarthritis.