DNA-Based Hydrogels for Musculoskeletal Reconstruction: Harnessing Dynamic Programmability and Multimodal Therapeutic Integration.

Musculoskeletal disorders, including bone fractures, osteoarthritis, and muscle injuries, represent a leading cause of global disability, revealing the urgency for advanced therapeutic solutions. However, current therapies face limitations including donor-site morbidity, immune rejection, and inadequate mimicry of dynamic tissue repair processes. DNA-based hydrogels emerge as transformative platforms for musculoskeletal reconstruction, with their sequence programmability, dynamic adaptability, and biocompatibility to balance structural support and biological functions. These hydrogels are classified into two categories: 1) DNA hydrogels, where DNA serves as the structural backbone; 2) DNA component-loaded hydrogels, integrating functional DNA elements like aptamers and therapeutic genes into non-DNA matrices. Through dynamic crosslinking strategies, primarily Watson-Crick base pairing, DNA networks achieve shear-thinning injectability and self-healing behaviors while providing binding sites for bioactive DNA components. Hybrid systems further enhance functionality by incorporating diverse materials to improve mechanical strength, drug delivery, and cellular guidance. This review systematically examines molecular design principles, classification frameworks, and preclinical applications of DNA-based hydrogels, aiming to bridge gaps between material innovation and clinical translation. Finally, current challenges are highlighted, and future directions to advance these intelligent biomaterials toward next-generation musculoskeletal therapies are proposed.