DNA-based nanomaterials represent a revolutionary approach in tissue engineering, offering precise control over scaffold architecture and bioactive signaling at the molecular level. Leveraging the programmability of DNA, researchers have developed nanostructures such as origami and nanotubes that mimic the extracellular matrix and guide cell behavior with unprecedented specificity. These constructs exploit DNA’s inherent properties, including molecular recognition, biocompatibility, and dynamic responsiveness to environmental cues, making them ideal for regenerative medicine applications like cartilage and liver regeneration.

The foundation of DNA nanotechnology lies in the predictable base-pairing rules of nucleic acids, enabling the design of complex 2D and 3D structures. DNA origami, for instance, involves folding a long single-stranded DNA scaffold into precise shapes using short staple strands. This technique allows the creation of nanostructures with sub-nanometer accuracy, which can be functionalized with peptides, growth factors, or other biomolecules to interact with cells in a controlled manner. Similarly, DNA nanotubes assemble from smaller DNA tiles or strands into tubular formations, providing structural support and directional cues for cell growth.

One of the most significant advantages of DNA nanomaterials is their molecular recognition capability. By incorporating specific DNA sequences or aptamers, these scaffolds can selectively bind to cell surface receptors or extracellular proteins, directing cellular adhesion, proliferation, and differentiation. For example, in cartilage regeneration, DNA origami scaffolds functionalized with chondrogenic factors like TGF-β3 have been shown to enhance mesenchymal stem cell differentiation into chondrocytes. The scaffolds’ precise spatial arrangement of signaling molecules mimics the native tissue environment, promoting the formation of organized collagen fibrils and proteoglycans essential for cartilage function.

Dynamic responsiveness is another critical feature of DNA-based scaffolds. Unlike static materials, DNA nanostructures can undergo conformational changes in response to stimuli such as pH, temperature, or specific biomolecules. This property enables on-demand release of therapeutic agents or adaptive mechanical support during tissue remodeling. In liver regeneration, pH-sensitive DNA hydrogels have been designed to degrade in the acidic microenvironment of injured tissue, releasing hepatocyte growth factor to stimulate parenchymal cell proliferation. The ability to modulate scaffold behavior in real time aligns with the dynamic nature of tissue repair processes.

DNA nanotubes have demonstrated particular promise in guiding axonal growth in neural tissue engineering, but their application extends to other tissues as well. For cartilage repair, tubular DNA structures can be aligned to replicate the anisotropic organization of collagen fibers in articular cartilage. Studies have shown that such aligned scaffolds improve the mechanical properties of engineered cartilage, with Young’s modulus values approaching those of native tissue. The nanotubes’ hollow interior can also be loaded with microRNAs or small molecules to further control chondrocyte behavior.

In liver regeneration, DNA origami has been used to create porous 3D scaffolds that support hepatocyte attachment and function. These scaffolds incorporate vascular endothelial growth factor (VEGF)-mimicking DNA sequences to promote angiogenesis, a critical factor in liver tissue engineering. The scaffolds’ porosity allows for efficient nutrient diffusion and waste removal, maintaining hepatocyte viability and albumin production at levels comparable to native liver tissue. Additionally, the incorporation of DNA-based logic gates enables scaffolds to respond to multiple biomarkers, such as elevated levels of reactive oxygen species, by releasing antioxidants or anti-inflammatory agents.

The mechanical properties of DNA nanomaterials can be tuned by adjusting crosslinking density or incorporating rigid motifs like double-crossover tiles. For cartilage applications, this tunability is crucial to match the compressive stiffness of native tissue, which ranges from 0.5 to 1.5 MPa. Hybrid DNA-collagen scaffolds have been developed to combine the bioactivity of collagen with the programmability of DNA, resulting in constructs that support both mechanical load-bearing and cell signaling. Similarly, in liver engineering, DNA nanostructures reinforced with gold nanoparticles have achieved elastic moduli suitable for mimicking the liver’s soft parenchyma.

Challenges remain in scaling up DNA nanomaterial production for clinical use, as large-scale synthesis and purification of complex DNA structures can be costly. However, advances in enzymatic DNA synthesis and error-correction techniques are addressing these limitations. Another consideration is the immune response to DNA scaffolds, although studies indicate that properly designed nanostructures with modified backbones (e.g., phosphorothioate DNA) exhibit minimal immunogenicity.

Future directions include the integration of DNA scaffolds with CRISPR-based gene editing tools to locally modulate cell behavior. For instance, DNA origami functionalized with guide RNA could deliver CRISPR components to specific cell populations within a tissue defect, enabling precise genetic reprogramming alongside structural support. Another avenue is the development of multi-layered DNA scaffolds that mimic the zonation of tissues like the liver, where different regions perform distinct metabolic functions.

The versatility of DNA nanomaterials extends beyond cartilage and liver regeneration, with potential applications in bone, cardiac, and skin tissue engineering. Their ability to encode complex biological information within a biocompatible, responsive framework positions them as a transformative platform for regenerative medicine. As fabrication techniques mature and our understanding of cell-nanomaterial interactions deepens, DNA-based scaffolds are poised to bridge the gap between synthetic materials and living tissues, offering new hope for patients with organ damage or degenerative diseases.