This review discusses the potential of RNA-based and cell-based therapies for the treatment of osteoarthritis (OA), a chronic and debilitating joint disease. The underlying mechanisms of OA are complex and involve multiple factors, including inflammation, cartilage loss, and bone remodeling. Current pharmacological treatments are limited and often provide only short-term relief, with limited impact on disease progression. RNA-based therapies, such as small interfering RNA (siRNA), microRNA (miRNA), and messenger RNA (mRNA), offer promising approaches to target specific genes and modulate gene expression. Chemical modifications and advanced delivery systems, such as nanoparticles, liposomes, and peptides, enhance the stability and efficacy of RNA therapeutics. CRISPR-Cas9 gene-editing technologies provide another avenue for precise genetic modifications to correct or silence disease-causing genes. Cell-based therapies, particularly engineered cells, have the potential to provide long-term, localized therapeutic effects. These therapies aim to enhance the function of cells by promoting the constitutive expression of anti-inflammatory and anabolic factors. Synthetic biology techniques, such as CRISPR-based platforms and chimeric protein engineering, allow for the design of "intelligent" cells that can respond dynamically to various inputs, including inflammation and matrix damage. These engineered cells can be used to produce therapeutic molecules or to target and eliminate cells contributing to OA progression. The review highlights the progress made in developing these technologies and their potential applications in OA treatment. It emphasizes the need for further research to overcome challenges such as safety, efficacy, and delivery methods, ultimately aiming to transform the management of OA by providing disease-modifying treatments that can delay or reverse disease progression.This review discusses the potential of RNA-based and cell-based therapies for the treatment of osteoarthritis (OA), a chronic and debilitating joint disease. The underlying mechanisms of OA are complex and involve multiple factors, including inflammation, cartilage loss, and bone remodeling. Current pharmacological treatments are limited and often provide only short-term relief, with limited impact on disease progression. RNA-based therapies, such as small interfering RNA (siRNA), microRNA (miRNA), and messenger RNA (mRNA), offer promising approaches to target specific genes and modulate gene expression. Chemical modifications and advanced delivery systems, such as nanoparticles, liposomes, and peptides, enhance the stability and efficacy of RNA therapeutics. CRISPR-Cas9 gene-editing technologies provide another avenue for precise genetic modifications to correct or silence disease-causing genes. Cell-based therapies, particularly engineered cells, have the potential to provide long-term, localized therapeutic effects. These therapies aim to enhance the function of cells by promoting the constitutive expression of anti-inflammatory and anabolic factors. Synthetic biology techniques, such as CRISPR-based platforms and chimeric protein engineering, allow for the design of "intelligent" cells that can respond dynamically to various inputs, including inflammation and matrix damage. These engineered cells can be used to produce therapeutic molecules or to target and eliminate cells contributing to OA progression. The review highlights the progress made in developing these technologies and their potential applications in OA treatment. It emphasizes the need for further research to overcome challenges such as safety, efficacy, and delivery methods, ultimately aiming to transform the management of OA by providing disease-modifying treatments that can delay or reverse disease progression.