Nanoparticle delivery systems for gene therapy of degenerative musculoskeletal diseases
8 affiliations
- 1Deparment of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Xiangya School of Medicine, Central South University, Changsha, Hunan, 410083, China
- 2Health Science Center, Peking University, Beijing, 100191, China
- 3Deparment of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- 4Department of Orthopedics, China-Japan Friendship Hospital, Beijing, 100029, China
- 5Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, 20500, Finland
- 6Deparment of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Corresponding author. Department of Orthopedics, Xiangya Hospital, Central South University, China.
- 7Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, 20500, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, 20014, Finland; Corresponding author. Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Finland.
- 8Department of Orthopedics, China-Japan Friendship Hospital, Beijing, 100029, China; Corresponding author. Department of Orthopedics, China-Japan Friendship Hospital, China.
Abstract
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.
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BibTeX
@article{chen2026nanoparticle,
title = {{Nanoparticle delivery systems for gene therapy of degenerative musculoskeletal diseases}},
author = {Xiaofei Chen and Jiale Sun and Wenqing Xie and Djandan Tadum Arthur Vithran and Qidong Zhang and Jessica M. Rosenholm and Yusheng Li and Hongbo Zhang and Cheng Huang},
journal = {Journal of Orthopaedic Translation},
year = {2026},
month = oct,
doi = {10.1016/j.jot.2026.101241},
url = {https://doi.org/10.1016/j.jot.2026.101241},
note = {CC BY},
}
RIS
TY - JOUR
TI - Nanoparticle delivery systems for gene therapy of degenerative musculoskeletal diseases
AU - Xiaofei Chen
AU - Jiale Sun
AU - Wenqing Xie
AU - Djandan Tadum Arthur Vithran
AU - Qidong Zhang
AU - Jessica M. Rosenholm
AU - Yusheng Li
AU - Hongbo Zhang
AU - Cheng Huang
PY - 2026
DA - 2026/10/25
JO - Journal of Orthopaedic Translation
DO - 10.1016/j.jot.2026.101241
UR - https://doi.org/10.1016/j.jot.2026.101241
AB - 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.
SN - 2214-031X
SN - 2214-0328
ER -