APTAMER-MODIFIED TETRAHEDRAL FRAMEWORK NUCLEIC ACID SYNTHESIZED WITH TGF-β3 TO PROMOTE CARTILAGE REPAIR IN OSTEOARTHRITIS BY ENHANCING CHONDROGENIC DIFFERENTIATION OF MESENCHYMAL STEM CELLS

Background: Osteoarthritis (OA) is the most common chronic joint disease with no cure at present . The repair of damaged articular cartilage has always been a vital part of OA treatment . Recent studies suggest that enhancing the recruitment of autologous mesenchymal stem cells (MSCs) to damaged cartilage could be a novel therapeutic strategy for OA . Transforming growth factor-beta 3 (TGF-β3) has been recognized as a potential therapeutic agent for OA owing to its protective effect. However, the application of TGF-β3 in the joint is limited by lacking MSCs targeting and low chondrogenesis efficiency . Objectives: To synthesize tetrahedral framework nucleic acid (TFNA), aptamer HM69 and TGF-β3 (HM69-TFNA@TGF-β3, termed HTT), and to evaluate chondrogenesis efficacy of HTT on MSCs in vitro and therapeutic effect of HTT in OA mice model. Methods: We confirmed the successful formation of HTT by polyacrylamide gel electrophoresis (PAGE), dynamic light scattering (DLS), and atomic force microscopy (AFM). MSCs chondrogenesis in vitro were evaluated by RT-qPCR, western blot and alcian blue staining. 60 mice at age of 8 weeks were induced into OA model by surgical destabilization of the medial meniscus (DMMs), The test mice received 10 ul doses of 250nM HTT, while controls received PBS solution. Functional recovery of the knees was evaluated via gait analysis, Von Frey test and histomorphological evaluation. Results: The successfully synthesized HTT was characterized by AFM. HTT perfectly retained the functions of TGF-β3 and TFNA in promoting the proliferation and migration of MSCs. After 7 and 21 days of chondrogenic induction, mRNA and protein expression levels of chondrogenic markers including SOX-9, aggrecan, and collagen II were significantly increased in HTT-treated MSCs group, indicating a positive chondrogenic differentiation and chondroprotective effects of HTT on MSCs. The effect of HTT was fully validated in DMM mice, including function recovery, pain relief and cartilage protection. Conclusion: We innovatively encoded an additional sequence HM69 and TGF-β3 on TFNA for better targeted recruitment of MSCs (HTT). HTT demonstrated its role in promoting chondrogenic differentiation of MSCs and cartilage protection in OA mice model, suggesting that it may be promising for OA MSCs-based therapy. REFERENCES: 1. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet 2019; 393 (10182): 1745-59. 2. Armiento AR, Alini M, Stoddart MJ. Articular fibrocartilage - Why does hyaline cartilage fail to repair? Adv Drug Deliv Rev 2019; 146 : 289-305. 3. Yu H, Huang Y, Yang L. Research progress in the use of mesenchymal stem cells and their derived exosomes in the treatment of osteoarthritis. Ageing Res Rev 2022; 80 : 101684. 4. Du X, Cai L, Xie J, Zhou X. The role of TGF-beta3 in cartilage development and osteoarthritis. Bone Res 2023; 11 (1): 2. Figure 1. Evaluation of the efficacy of TGF-β3, TFNA, and HTT in improving cartilage degeneration in osteoarthritis after DMM surgery. Representative images of (a) Safranin-O/Fast green staining and (b) Toluidine blue staining of the knee joints after different treatments. Cartilage lesions were highlighted by black arrows in (a) and yellow arrows in (d), respectively. b-c. OARSI scores were measured according to the histological analysis of the samples collected at 6 weeks and 10 weeks post-surgery, respectively. e. cartilage area were measured according to the histological analysis of the samples collected at 6 weeks and 10 weeks post-surgery. Statistical analysis: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Acknowledgements: NIL. Disclosure of Interests: None declared. DOI: 10.1136/annrheumdis-2024-eular.1727 Keywords: Targeted synthetic drugs, Cartilage Citation: , volume 83, supplement 1, year 2024, page 1409Session: Osteoarthritis and other mechanical musculoskeletal problems (Publication Only)

Targeted synthetic drugs, Cartilage