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Injectable microenvironment-responsive hydrogels encapsulating engineered NF-κB-targeting circular RNA for
Meng Li1, Xumiao Jia1, Penghui Lai2
1Shaanxi 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.
A novel drug delivery system using circular RNA (circRNA) effectively targets osteoarthritis by inhibiting inflammation and promoting cartilage repair. This innovative approach shows promise for improved osteoarthritis treatment and management.
Area of Science:
- Biomaterials Science
- Molecular Biology
- Rheumatology
Background:
- Osteoarthritis (OA) involves cartilage degeneration and bone imbalance, posing treatment challenges.
- Current topical OA treatments struggle with efficacy, stability, and rapid clearance.
- Overactive NF-κB signaling is a key factor in OA pathogenesis.
Purpose of the Study:
- To develop an environment-responsive intelligent drug delivery system for OA.
- To target and inhibit NF-κB signaling in OA using a novel circRNA construct.
- To evaluate the therapeutic efficacy of the developed system in vitro and in vivo.
Main Methods:
- Engineered a circular RNA (circRNA) carrying a P65 super repressor gene (srIκBα).
- Encapsulated circ-srIκBα within lipid nanoparticles (LNPs) and embedded in a silk fibroin hydrogel (SHC).
- Utilized matrix metalloproteinase (MMP)-sensitive peptides for hydrogel cross-linking, creating circ-srIκBα@LNP-SHC.
Main Results:
- The circ-srIκBα@LNP-SHC system demonstrated targeted delivery to chondrocytes and fibroblast-like synoviocytes (FLS) in vitro.
- Significantly inhibited NF-κB signaling in vitro and suppressed OA-related inflammatory mediators and matrix-degrading enzymes in vivo.
- Showcased superior anti-OA efficacy, cartilage repair, and reversal of OA-associated gene expression in an OA rat model.
- Validated therapeutic effects using ex vivo cultured human OA cartilage.
Conclusions:
- The developed environment-responsive drug delivery system based on circ-srIκBα offers a novel strategy for OA management.
- The system exhibits enhanced cell specificity, stability, and low immunogenicity.
- This approach holds significant potential for effective OA treatment and cartilage repair.
