Functional nucleic acid Hydrogels: Paving the way for Next-generation bone and cartilage regeneration.

Functional nucleic acid hydrogels represent a transformative approach in bone and cartilage tissue engineering, integrating the programmability of nucleic acids with the biomimetic properties of hydrogels to overcome clinical challenges in skeletal regeneration. These advanced materials leverage DNA- and RNA-based strategies to orchestrate the three core elements of tissue engineering: stem cell recruitment and differentiation, bioactive scaffolds, and controlled bioactive agents delivery. DNA hydrogels are categorized as pure (crosslinked or base-paired) and hybrid (functionalized with plasmid DNA, aptamers, or tetrahedral framework nucleic acids (tFNA)). They enable precise spatiotemporal control over therapeutic molecule release, mechanical microenvironment modulation, and immunoregulation. For instance, tFNA-hydrogel composites enhance vascularized osteogenesis through targeted delivery of therapeutic agents, while aptamer-modified hydrogels promote stem cell recruitment and boost scaffold bioactivity. RNA-loaded systems, particularly carriers of non-coding RNAs (miRNA, siRNA, circRNA) in hydrogels or extracellular vesicles, regulate critical osteogenic and chondrogenic pathways such as Wnt/β-catenin and BMP/Smad. Engineered microspheres ensure sustained, stimuli-responsive release, overcoming RNA instability. Despite promising preclinical outcomes in treating diabetic bone defects, osteoarthritis, and critical-sized fractures, significant hurdles persist, including limited nucleic acid stability within hydrogels, suboptimal transfection efficiency, and unresolved long-term biocompatibility of degradation products, demanding targeted solutions for clinical translation. Future advancements require optimizing material design for clinical translation, emphasizing synergistic integration of nucleic acid nanotechnology with dynamic hydrogel matrices to achieve functional regeneration of complex skeletal tissues.