Tetrahedral framework nucleic acids for improving wound healing

Abstract

Wounds are one of the most common health issues, and the cost of wound care and healing has continued to increase over the past decade. In recent years, there has been growing interest in developing innovative strategies to enhance the efficacy of wound healing. Tetrahedral framework nucleic acids (tFNAs) have emerged as a promising tool for wound healing applications due to their unique structural and functional properties. Therefore, it is of great significance to summarize the applications of tFNAs for wound healing. This review article provides a comprehensive overview of the potential of tFNAs as a novel therapeutic approach for wound healing. In this review, we discuss the possible mechanisms of tFNAs in wound healing and highlight the role of tFNAs in modulating key processes involved in wound healing, such as cell proliferation and migration, angiogenesis, and tissue regeneration. The targeted delivery and controlled release capabilities of tFNAs offer advantages in terms of localized and sustained delivery of therapeutic agents to the wound site. In addition, the latest research progress on tFNAs in wound healing is systematically introduced. We also discuss the biocompatibility and biosafety of tFNAs, along with their potential applications and future directions for research. Finally, the current challenges and prospects of tFNAs are briefly discussed to promote wider applications.

Keywords: DNA nanomaterials; Tetrahedral framework nucleic acids; Tissue regeneration; Wound healing.

Fig. 1

A diagram of the wound healing process. PDGF: platelet-derived growth factor; FGF: fibroblast growth factor; EGF: epidermal growth factor; TGF: transforming growth factor; MCP-1: monocyte chemotactic protein 1. Reprinted with permission from Ref. [8]

Fig. 2

Tetrahedral DNA nanostructures play a vital role in the repair and regeneration of several tissues. Reprinted with permission from Ref. [23]

Fig. 3

tFNAs as a delivery carrier with antibacterial activity. (A) Schematic representation of nanotheranostic DPAu/AMD synthesis. DP: DNA nanopyramid; AMD: Actinomycin D. Reprinted with permission from Ref. [59]. (B) DPAu/AMD-treated E. coli and S. aureus cells were stained with live/dead cell stain to validate the killing effect. E. coli: Escherichia coli; S. aureus: Staphylococcus aureus. Reprinted with permission from Ref. [59]. (C) tFNAs-Antibiotic Compound (TAC) improved the survival rate of severely infected mice and promoted the healing of local infections by the excellent delivery capability of tFNAs. tFNAs: tetrahedral framework nucleic acids. Reprinted with permission from Ref. [60]. (D) Confocal laser scanning microscopy images of bacterial uptake of tFNAs and TACs in MRSA at 90 min. Reprinted with permission from Ref. [60]. (E) Confocal laser scanning microscopy images of bacterial uptake of tFNAs and TACs in E. coli at 90 min. ssDNA: single-stranded DNA. Reprinted with permission from Ref. [60]

Fig. 4

tFNAs as a delivery carrier with antibacterial activity. (A) tFNAs increase the erythromycin efficiency by delivering it more inside the cells. Ery: erythromycin. Reprinted with permission from Ref. [106]. (B) Confocal laser scanning microscopy images of bacterial uptake of tFNAs and tFNAs-Ery in E. coli at 90 min. Reprinted with permission from Ref. [106]. (C) Flow cytometry analysis of the uptake rates of E. coli incubated with ssDNA, tFNAs and tFNAs-Ery. Reprinted with permission from Ref. [106]. (D) Schematic representation of how tFNAs deliver ASOs to inhibit the formation of bacterial biofilms by targeting genes related to EPS synthesis. ASOs: antisense oligonucleotides. Reprinted with permission from Ref. [107]. (E) Dual-label imaging and three-dimensional visualization of EPS (red) and bacteria (green) in S. mutans biofilms after treatment with ASOs-tFNA at 500 nM and 750 nM. Reprinted with permission from Ref. [107]

Fig. 5

tFNAs promote regulation of cell proliferation and migration. (A) tFNAs promote corneal epithelial wound healing. Reprinted with permission from Ref. [25]. (B) An in vitro scratch wound healing assay detected the effect of tFNAs at different concentrations on the migration of human corneal epithelial cells (HCECs). Reprinted with permission from Ref. [25]. (C) Schematic diagram of the regulatory effects of tFNAs on TGF-β1-induced fibrogenesis via interaction with Smad2/Smad3 signals. Reprinted with permission from Ref. [28]. (D) Images of scratch tests on HaCaT cells treated with different concentrations of tFNAs at 0 h, 6 h, and 24 h. Reprinted with permission from Ref. [28]. (E) Statistical analysis of scratch tests on HaCaT cells and HSF cells. Reprinted with permission from Ref. [28]

Fig. 6

tFNAs promote regulation of cell proliferation and migration. (A) Schematic diagram of the regulatory effects of tFNAs on TGF-β1-induced fibrogenesis via interaction with Smad2/Smad3 signals. ROS: reactive oxygen species; EMT: epithelial-mesenchymal transition; ECM: extracellular matrix. Reprinted with permission from Ref. [75]. (B) TFNAs reduce TGF-β1-induced α-SMA expression in RLE-6TN cells. TGF-β1: Transforming growth factor beta 1. Reprinted with permission from Ref. [75]. (C) tFNAs reduce skin fibrosis by inhibiting the pyroptosis pathway. Reprinted with permission from Ref. [128]. (D) Western blotting (WB) analysis of the α-SMA, fibronectin, collagen I, E-cadherin, and Smad2/3 expression levels. Reprinted with permission from Ref. [128]. (E) Immunofluorescence (IF) micrographs of TGF-β- and tFNA-treated HaCaT cell 3D reconstruction diagrams and statistical analyses of IF and WB results for protein expression. Reprinted with permission from Ref. [128]

Fig. 7

Angiogenesis-promoting effects of tFNAs. (A) tFNAs promote endothelial cell proliferation, migration, and angiogenesis via the Notch signaling pathway. TDN: tetrahedral DNA nanostructures. Reprinted with permission from Ref. [136]. (B) TDNs promoted tube formation of endothelial cells (ECs). Reprinted with permission from Ref. [136]. (C) Measurement of master junctions and master segments; Reprinted with permission from Ref. [136]. (D) Schematic diagram of the antioxidative and angiogenesis-promoting effects of tFNAs in diabetic wound healing. Reprinted with permission from Ref. [72]. (E) Tube formation assay. AGEs: advanced glycation end products. Reprinted with permission from Ref. [72]. (F) Semiquantification analysis of the major junctions and lengths of formed vessels. Reprinted with permission from Ref. [72]

Fig. 8

Angiogenesis-promoting effects of tFNAs. (A) Angiogenic aptamer-modified tFNAs promote angiogenesis in vitro and in vivo. Reprinted with permission from Ref. [124]. (B) Tube-formation assay for evaluating vascularization after treatment with nanoparticles. VEGF: Vascular endothelial growth factor. Reprinted with permission from Ref. [124]. (C) Cellular uptake of FAM-labeled peptides and FAM-labeled p@tFNA. Reprinted with permission from Ref. [74]. (D) Tube formation assay. p@tFNAs: tetrahedral framework nucleic acid (tFNA)-based peptide. AGEs: advanced glycation end products. Reprinted with permission from Ref. [74]. (E) Analysis of tube nodes, junctions, meshes, total meshes area, branching lengths and branching intervals of formed vessels. p@tFNAs: tetrahedral framework nucleic acid (tFNA)-based peptide; AGEs: advanced glycation end products. Reprinted with permission from Ref. [74]