Nanoparticle delivery systems for gene therapy of degenerative musculoskeletal diseases

Degenerative musculoskeletal diseases (DMDs) are a group of chronic conditions characterized by the progressive deterioration of tissue structure and function, primarily affecting the articular cartilage, bones, tendons, and ligaments. With global aging populations, the rising prevalence of these disorders presents a growing public health challenge. Current treatments for DMDs are limited by substantial drug side effects and restricted therapeutic efficacy. Gene therapy has emerged as a promising alternative for addressing these conditions. Nanoparticles are essential for overcoming intracellular and extracellular barriers in nucleic acid delivery. Recent technological advances have led to novel nanomaterials and strategies, which have enabled safer and more efficient gene therapy. This review comprehensively analyzes the role of nanoparticle delivery systems in enabling effective gene-based interventions for major DMDs. First, we analyze the main gene therapies for various DMDs. Next, we systematically summarize recent advances in nanocarrier platforms and delivery strategies targeting osteoporosis, osteoarthritis, intervertebral disc degeneration, and tendon diseases. Finally, we discuss key challenges and future directions, offering a roadmap to advance nanoparticle delivery therapeutics toward clinical impact. This synthesis uniquely bridges nanoparticle delivery design with disease-specific pathophysiology, providing strategic guidance for overcoming translational barriers through emerging technologies including AI-driven carrier optimization and organ-on-chip platforms. Across these diseases, no carrier is universally optimal: systemic bone delivery prioritizes circulation stability and cell-selective targeting, whereas local delivery to cartilage, intervertebral discs, and tendons requires a balance among tissue retention, matrix penetration, cellular uptake, and controlled release. Current evidence remains predominantly preclinical and frequently demonstrates tissue accumulation without fully establishing intact-cargo delivery, functional target engagement, long-term safety, or manufacturability. This review therefore links nanoparticle design to disease-specific barriers and identifies the evidence required for clinical translation. The Translational Potential of this Article. This review focuses on the clinical translational potential of nanoparticle-based delivery systems for gene therapy in degenerative musculoskeletal diseases (DMDs). Addressing the unique physiological and pathological barriers of specific musculoskeletal tissues (such as bone, cartilage, intervertebral discs, and tendons), this article systematically summarizes targeting and sustained-release strategies designed to enhance delivery efficiency and overcome tissue-specific obstacles. Furthermore, this study highlights future perspectives, including artificial intelligence (AI)-driven carrier optimization, organ-on-a-chip models, and multimodal combination therapies integrating biomaterials and cells. By addressing the limitations of conventional therapies that merely alleviate symptoms without reversing tissue degeneration, this review provides a robust theoretical foundation and a clear translational roadmap for the development of precise, safe, and long-lasting gene therapy regimens for DMDs.