Application strategies of DNA hydrogels for tissue repair

Abstract

BACKGROUND: DNA hydrogels possess thermal resilience, thixotropy, enzyme responsiveness, and degradability. Further functionalization with chemical modifications, peptides, aptamers, and other elements can endow hydrogels with unique responsiveness, demonstrating their immense potential as smart materials. OBJECTIVE: To summarize fabrication strategies, functional properties, and applications of DNA hydrogels. METHODS: PubMed and CNKI databases were searched using "DNA hydrogel, tissue engineering, tissue regeneration" as English and Chinese search terms. Based on inclusion criteria, 76 relevant articles were selected for in-depth analysis. RESULTS AND CONCLUSION: Current research has established diverse preparation methods for DNA hydrogels, including: nanomodule assembly, rolling circle amplification, and hybridization chain reaction for pure DNA hydrogels; grafting DNA molecules onto polymers and adding crosslinkers to form hybrid DNA hydrogels; interpenetrating polymer networks with DNA nanomodule networks; and physical crosslinking. Modular self-assembled hydrogels often exhibit shear-thinning and self-healing capabilities, making them injectable for irregular wounds and bone regeneration with good filling capacity. DNA hydrogels can load, protect, and deliver various bioactive components. They can mimic the extracellular matrix, support 3D cell culture, and serve as delivery platforms for stem cell therapy in bone repair and neural regeneration. Additionally, DNA hydrogels enable theranostics, intelligently responding to different disease requirements. However, clinical translation faces challenges: immunogenicity remains controversial, and laboratory-scale synthesis is costly and limited. Future efforts should focus on integrating bioactive molecules to enhance therapeutic efficacy and improving cost-effectiveness.

1. Introduction

In the field of tissue engineering, research efforts are dedicated to finding suitable scaffold materials that mimic the extracellular matrix to promote the migration and growth of peripheral cells, while continuously releasing loaded therapeutic molecules to facilitate damaged tissue repair. Hydrogels are a class of three-dimensional networks formed by polymer chains through physical or chemical crosslinking, capable of absorbing and retaining large amounts of water, loading bioactive components, and filling defect sites, making them ideal scaffold materials. Currently, a wide variety of materials are used for hydrogel synthesis, including polyacrylamide [1], polyvinyl alcohol [2], polyethylene glycol [3], and polyacrylic acid [4]. However, synthetic polymers such as polyacrylamide have toxic degradation products and suboptimal biocompatibility, limiting their biomedical applications. This drawback can be mitigated by using natural materials, such as alginate [5], chitosan [6], collagen [7], dextran [8], gelatin [9], hyaluronic acid, and silk fibroin [10-11], which generally exhibit low toxicity and weak immunogenicity and have been widely developed as wound dressings and implantable scaffolds. Typically, hydrogels formed from these biopolymers have relatively simple structures, and even with chemical modification, they may not fully meet the demands for intelligent and personalized repair of various tissue injuries.

DNA hydrogels are gels formed by DNA molecules as structural units or crosslinkers, retaining the conventional properties of hydrogels while their pore structure more closely resembles the extracellular matrix, facilitating the transport and removal of nutrients and metabolic waste. DNA can form gels through non-covalent interactions, and such dynamic crosslinking allows for easier diffusion of macromolecules, proteins, and even extracellular vesicles within the gel [12-13]. Based on the inherent properties of DNA, DNA hydrogels exhibit thermal resilience, thixotropy, enzyme responsiveness, and degradability [14]. Furthermore, functional elements such as chemical modifications [15], peptides [16], and aptamers [17] can be introduced to confer specific responsiveness, demonstrating their immense potential as smart materials. DNA hydrogels have been widely studied for applications in biosensing [18-19], drug delivery [20], tissue engineering [21-22], cell capture, and 3D culture [18,23-24], as illustrated in Figure 1. This review introduces the construction methods and properties of DNA hydrogels, summarizes recent applications in tissue repair, and discusses the clinical potential of DNA hydrogels as intelligent materials.