The advent of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and associated Cas endonuclease technology represents a revolutionary development in molecular biology and regenerative medicine. Initially discovered as part of a bacterial adaptive immune response, the CRISPR-Cas Systems has been harnessed for precise genome editing, allowing site-specific double-stranded DNA cleavage under the guidance of a synthetic single-guide RNA (sgRNA)(1). This programmable tool has rapidly transformed basic and translational science, enabling efficient and cost-effective manipulation of genomic sequences in eukaryotic cells. Its broad utility in disease modeling, gene correction, and tissue engineering has catalyzed novel therapeutic strategies across a range of medical disciplines, including oncology, neurology, hematology, and increasingly, orthopaedics and musculoskeletal (MSK) medicine(2).

Musculoskeletal diseases constitute a major global burden of disease, accounting for substantial morbidity, chronic disability, and healthcare expenditure. Disorders such as osteoarthritis, intervertebral disc degeneration, muscular dystrophies, and rare skeletal dysplasias are characterized by complex pathogenesis involving genetic predispositions, mechanical stressors, inflammatory cascades, and impaired tissue regeneration(3,4). Conventional orthopedic therapies—ranging from pharmacological symptom management to surgical joint reconstruction—are often limited by their inability to address the molecular underpinnings of disease progression. Consequently, there is an increasing need for biologically driven interventions that can modify disease trajectories, enhance tissue repair, and potentially provide curative outcomes.

In this context, CRISPR-Cas gene editing offers a paradigm shift. Preclinical studies have demonstrated the successful use of CRISPR to knock out deleterious genes such as matrix metalloproteinase-13 (MMP-13), a catabolic enzyme implicated in cartilage breakdown in osteoarthritis(5); to upregulate regenerative transcription factors like SOX9 for enhanced chondrogenesis(6); and to model rare genetic skeletal disorders such as osteogenesis imperfecta through targeted mutation of COL1A1 and COL1A2 genes(7). The technology has also been applied to enhance the biological performance of mesenchymal stem cells (MSCs), either by silencing senescence pathways (e.g., p16INK4a) or promoting lineage-specific differentiation(8). These advances underscore the potential of CRISPR-Cas9 not only as a tool for understanding musculoskeletal pathophysiology, but also as a therapeutic modality to regenerate bone, cartilage, muscle, and tendon tissues.

Recent years have also witnessed efforts to integrate CRISPR-Cas with biomaterials science and 3D bioprinting. Gene-edited cells seeded into scaffolds or hydrogels are being explored to create bioengineered constructs capable of structural and functional joint restoration(9,10). Furthermore, nanotechnology-enabled delivery systems—such as lipid nanoparticles and viral vectors—have been developed to enhance the tissue specificity and efficiency of CRISPR delivery in vivo, including within load-bearing musculoskeletal environments(11). These multi-modal strategies represent the frontier of regenerative orthopaedics, with implications for both acute repair and chronic disease modification.

However, the translation of CRISPR-Cas Systems into clinical musculoskeletal care is still in its infancy. Despite promising results from ex vivo and small-animal studies, challenges remain regarding off-target effects, immunogenicity of Cas proteins, and efficient delivery to avascular tissues such as cartilage. There is also limited standardization of experimental protocols, variable outcome reporting, and a lack of longitudinal data on the safety and durability of gene edits. Moreover, ethical concerns surrounding germline editing and the regulatory complexity of somatic gene therapies continue to influence clinical trial readiness in this field(12).

To our knowledge, no scoping review to date has systematically mapped the application of CRISPR-Cas Systems within the domain of orthopaedics and musculoskeletal medicine. Given the exponential growth in the number of peer-reviewed publications, the interdisciplinary nature of this field, and the urgent need to identify translational opportunities, such a review is both timely and necessary.