Abstract
Gene therapy is identified as a powerful strategy to overcome the limitations of traditional therapeutics to achieve satisfactory effects. However, various challenges related to the dosage form, delivery method, and, especially, application value, hampered the clinical transition of gene therapy. Here, aiming to regulate the cartilage inflammation and degeneration related abnormal IL‐1β mRNA expression in osteoarthritis (OA), the interference oligonucleotides is integrated with the Au nanorods to fabricate the spherical nucleic acids (SNAs), to promote the stability and cell internalization efficiency. Furthermore, the complementary oligonucleotides are grafted onto hyaluronic acid (HA) to obtained DNA‐grafted HA (DNAHA) for SNAs delivery by base pairing, resulting in significantly improved injectability and bio‐stability of the system. After loading SNAs, the constructed DNAHA‐SNAs system (HA‐SNAs) performs a reversible NIR‐triggered on‐demand release of SNAs by photo‐thermal induced DNA dehybridization and followed by post‐NIR in situ hybridization. The in vitro and in vivo experiments showed that this system down‐regulated catabolic proteases and up‐regulated anabolic components in cartilage over extended periods of time, to safeguard the chondrocytes against degenerative changes and impede the continual advancement of OA.
Highlights
As one of the most common degenerative diseases, osteoarthritis (OA) has become a public health challenge in the current aging society, with worldwide estimates indicating that 250 million people are affected nowadays.[1]
In order to evaluate the potential clinical application of the NIR light-triggered thermal-assisted gene therapy system based on hyaluronic acid (HA), we performed in vitro and in vivo experiments to demonstrate whether HA-spherical nucleic acids (SNAs) irradiated with NIR light protect the chondrocytes from the oxidative stress-induced degeneration and impede the development of OA
Functionalized singlestranded DNA (5′-GCTCCGAGATGAATTTTT-3′) with N3 at the 3′-tuminus, which was used as the sense strand for hybridizing with the antisense DNA strands on SNAs, was conjugated onto the DBCO modified HA by strain-promoted alkyne-azide cycloaddition to obtain the DNA-grafted HA (DNAHA)
Summary
As one of the most common degenerative diseases, osteoarthritis (OA) has become a public health challenge in the current aging society, with worldwide estimates indicating that 250 million people are affected nowadays.[1]. Hyaluronic acid (HA) is shown in numerous recent studies to be a viable intra-articular treatment option and universally applied in clinic, showing great lubrication function in joint cavity and long-term improvement in both pain and function.[17] HA-based biomaterials, such as hydrogels,[18,19,20,21] nanocarriers,[22,23,24,25] and microscaffolds,[26,27,28] are emerging as appealing starting materials due to HA’s biocompatibility, native biofunctionality, biodegradability, non-immunogenicity, and versatility.[29] many of them degrade very fast and lack high-dose injectability, which limits their potential biomedical applications. In the presence of the Au NRs,[31] the formed DNAHA-SNAs system (termed as HASNA) can be dissembled by NIR light-induced thermo effect, achieving controlled SNAs release Based on these premises, a NIR light-triggered inflammatory gene-targeted drug delivery system is designed and fabricated by incorporating DNAHA and SNAs by DNA hybridization for local injectable gene treatment of OA, as shown in Scheme 1. We hypothesize that the NIR light-triggered thermal-assisted gene therapy system developed here, HA-SNAs, can be employed intra-articularly as an effective injectable agent to inhibit the development of OA
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