Injectable microenvironment-responsive hydrogels encapsulating engineered NF-κB-targeting circular RNA for osteoarthritis therapy

Meng Li; Xumiao Jia; Penghui Lai; Yuqian Ma; Fei Li; Lingyan Yang; Siyuan Zhang; Chongfei Yang; Yu Luo; Qinhao Wang

doi:10.1016/j.jconrel.2025.114039

Injectable microenvironment-responsive hydrogels encapsulating engineered NF-κB-targeting circular RNA for osteoarthritis therapy

J Control Release. 2025 Jul 11:114039. doi: 10.1016/j.jconrel.2025.114039. Online ahead of print.

Authors

Meng Li¹, Xumiao Jia¹, Penghui Lai², Yuqian Ma³, Fei Li⁴, Lingyan Yang⁵, Siyuan Zhang⁵, Chongfei Yang⁶, Yu Luo⁷, Qinhao Wang⁸

Affiliations

¹ Shaanxi Key Laboratory of Optoelectronic Functional Materials and Devices, School of Materials Science and Chemical Engineering, Xi'an Technological University, Xi'an, Shaanxi 710021, China; Department of Biochemistry and Molecular biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
² Mirco- and Nano-technology Research Center, State Key Laboratory for Manufacturing Systems Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
³ Department of Biochemistry and Molecular biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; College of Life Sciences, Yan'an University, Yan'an, Shaanxi 716000, China.
⁴ Department of Biochemistry and Molecular biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710000, China.
⁵ Department of Biochemistry and Molecular biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China.
⁶ Institute of Orthopaedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: cfyang@fmmu.edu.cn.
⁷ Mirco- and Nano-technology Research Center, State Key Laboratory for Manufacturing Systems Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China. Electronic address: yuluo825@xjtu.edu.cn.
⁸ Department of Biochemistry and Molecular biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: bcmbwang@fmmu.edu.cn.

PMID: 40653275
DOI: 10.1016/j.jconrel.2025.114039

Abstract

Osteoarthritis (OA) is a prevalent joint disease characterized by cartilage degeneration and an imbalance in subchondral bone homeostasis. Effective topical treatment of OA remains challenging due to the insufficient long-term efficacy, instability, and rapid clearance of therapeutic agents. In this study, we targeted the overactive NF-κB signaling in OA by introducing a P65 super repressor gene (srIκBα) as a circular RNA (circRNA), encapsulated within modified lipid nanoparticles (LNPs), and embedded in a silk fibroin composite hydrogel (SHC) cross-linked with matrix metalloproteinase (MMP)-sensitive substrate peptides. Consequently, we developed an environment-responsive intelligent drug delivery system, namely, circ-srIκBα@LNP-SHC, and the performance of this system was evaluated both in vitro and in vivo. It demonstrated potent targeting effects on chondrocytes and fibroblast-like synoviocytes (FLS) in vitro, with significantly inhibiting NF-κB signaling. In an OA rat model, circ-srIκBα@LNP-SHC exhibited superior anti-OA efficacy and cartilage repair capability, and markedly suppressed the expression of OA-related inflammatory mediators and matrix-degrading enzymes, and reversed the OA-associated gene expression profile. The therapeutic effect was further validated using human OA cartilage cultured ex vivo. In conclusion, our environmentally responsive drug delivery system based on circ-srIκBα shows significant potential for OA treatment, offering improved cell specificity, stability, and low immunogenicity, which may provide a novel strategy for OA management.

Keywords: Drug delivery; NF-κB super repressor; Osteoarthritis; Silk fibroin; circRNA.