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Review
. 2022 Jun 28;8(1):e10343.
doi: 10.1002/btm2.10343. eCollection 2023 Jan.

miRNA-encapsulated abiotic materials and biovectors for cutaneous and oral wound healing: Biogenesis, mechanisms, and delivery nanocarriers

Asmita Deka Dey  1 , Satar Yousefiasl  2 , Arun Kumar  1 , Farnaz Dabbagh Moghaddam  3   4 , Ilnaz Rahimmanesh  5 , Mohamadmahdi Samandari  6 , Sumit Jamwal  7 , Aziz Maleki  8   9   10 , Abbas Mohammadi  11 , Navid Rabiee  12   13 , Ana Cláudia Paiva-Santos  14   15 , Ali Tamayol  6 , Esmaeel Sharifi  16 , Pooyan Makvandi  17   18
Affiliations
Review

miRNA-encapsulated abiotic materials and biovectors for cutaneous and oral wound healing: Biogenesis, mechanisms, and delivery nanocarriers

Asmita Deka Dey et al. Bioeng Transl Med. .

Abstract

MicroRNAs (miRNAs) as therapeutic agents have attracted increasing interest in the past decade owing to their significant effectiveness in treating a wide array of ailments. These polymerases II-derived noncoding RNAs act through post-transcriptional controlling of different proteins and their allied pathways. Like other areas of medicine, researchers have utilized miRNAs for managing acute and chronic wounds. The increase in the number of patients suffering from either under-healing or over-healing wound demonstrates the limited efficacy of the current wound healing strategies and dictates the demands for simpler approaches with greater efficacy. Various miRNA can be designed to induce pathway beneficial for wound healing. However, the proper design of miRNA and its delivery system for wound healing applications are still challenging due to their limited stability and intracellular delivery. Therefore, new miRNAs are required to be identified and their delivery strategy needs to be optimized. In this review, we discuss the diverse roles of miRNAs in various stages of wound healing and provide an insight on the most recent findings in the nanotechnology and biomaterials field, which might offer opportunities for the development of new strategies for this chronic condition. We also highlight the advances in biomaterials and delivery systems, emphasizing their challenges and resolutions for miRNA-based wound healing. We further review various biovectors (e.g., adenovirus and lentivirus) and abiotic materials such as organic and inorganic nanomaterials, along with dendrimers and scaffolds, as the delivery systems for miRNA-based wound healing. Finally, challenges and opportunities for translation of miRNA-based strategies into clinical applications are discussed.

Keywords: abiotic nanomaterials; chronic wounds; miRNA delivery; nanobiovectors; oral mucosa wound; viral and nonviral nanocarriers.

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Conflict of interest statement

The authors declare no potential conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Graphic representation of the biogenesis of miRNA. RNA polymerase II/III carries out miRNA transcription from genomic DNA to construct the pri‐miRNA in the nucleus. Drosha and its cofactor DGCR8 then cleave the pri‐miRNA to form Pre‐miRNA. Exportin‐5 and Ran‐GTP transports the pre‐miRNA into the cytoplasm. In the cytoplasm, the Dicer and TRBP recognize pre‐miRNA and cut into dsRNA which matures and thus resulting in a miRNA duplex. Matured miRNA duplex is loaded in the RISC to form the mature miRNA molecules. AGO, argonaute; DGCR8, DiGeorge syndrome critical region 8; Pre‐miRNA, precursor miRNA; Pri‐miRNA, primary miRNA; RISC, RNA‐induced silencing complex; TRBP, TAR RNA binding protein
FIGURE 2
FIGURE 2
Targeted pathways of some anti‐inflammatory miRNAs are observed to control and regulate the inflammatory response. In addition to activating some of the mechanisms involved in this process, various miRNAs are involved in inflammatory processes and inflammatory diseases by creating significant loops of negative feedback. AP1, activator protein 1; GATA3, GATA binding protein 3; IFNγ, interferon gamma; IL, interleukin; LPS, lipopolysaccharide; MCP1, monocyte chemoattractant protein‐1; NF‐kB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; NOD2, nucleotide‐binding oligomerization domain‐containing protein 2; STAT3, signal transducer and activator of transcription 3; STAT6, signal transducer and activator of transcription 6; Th1, T helper type1; Th17, T helper type17; Th2, T helper type2; TLR, Toll‐like receptor; TNFα, tumor necrosis factor alpha; VCAM‐1, vascular cell adhesion molecule 1
FIGURE 3
FIGURE 3
miRNA plays a role in the periodontal tissue regeneration process. (a) The top 20 most variated miRNA expression profiles in day 5 of human gingiva wound healing. 1a–9a displays healthy gingiva, and 1b–9b displays the healing gingiva of the identical person. The colors of this heatmap exhibit the upregulation and downregulation with green and red, respectively. Reproduced from Reference with permission from Wiley. (b) The expression of miR‐150, miR‐200b, miR‐223, miR‐144, miR‐379, and miR‐222 in three samples of inflamed and noninflamed gingiva using real‐time PCR (*p < 0.01). Reproduced from Reference under open access license. (c) Schematic on the regulative role of miRNA (i.e., promote or inhibit) on the innate immune cells (i.e., macrophages, neutrophils, and dendritic cells), besides adaptive immune cells, including T and B lymphocytes. IL, interleukin; miR, miRNA
FIGURE 4
FIGURE 4
Comparison between the skin and oral mucosa in normal condition and during wound healing. (a) Schematic on the major differences of skin and oral mucosa wound healing process. (b) miRNA expression profile of skin and oral mucosa in the normal condition; (i) applying miR‐Seq analysis, the top 5% most plentiful miRNA species calculated 81.64% for skin epithelium and 77.8% for oral mucosa epithelium. (ii) The top 10 mostly expressed miRNA in the skin (iii) and oral mucosa (palate). (c) miRNA expression profile variation within the skin and oral mucosa wound healing process. Variation in the expression level of 10 primarily expressed miRNAs of skin and oral mucosa through the wound healing process, displayed as the percent of the miRNAome. miR, miRNA. Parts (b) and (c) are reproduced from Reference under the terms of CC‐BY license open access
FIGURE 5
FIGURE 5
Schematic illustration on viral‐based transgene delivery mechanism for gene therapy. In viral‐based gene delivery systems, genetically engineered viruses are used to infect target cells for gene transfer. Nuclear entry is followed by efficient transgene expression, introducing the viral vectors as powerful vehicles for gene transfer. Abbreviations; RISC: RNA‐induced silencing complex.
FIGURE 6
FIGURE 6
Notch/ Jagged1 signaling is a major regulator of epidermal stem cell proliferation differentiation through Hes1 expression. Hes1 downregulation via miR‐203 could be a major molecular mechanism in wound healing and scar formation. Anti‐miR‐203 treatment promoted wound closure and decreased scar formation rate in vivo. Direct injection of the anti‐miR‐203 into the tissue around the wound resulted in a significant reduction in scar thickness and index compared to the control group at day 14. *p < 0.05. ESC, epidermal stem cell; Hes 1, hairy/enhancer of split‐1 gene; MFB, myofibroblasts; NICD, notch intracellular domain. Right panel was reproduced from Reference under open access license
FIGURE 7
FIGURE 7
miRNA conjugated metallic NPs enhance wound healing. (a) Schematic on the preparation of miRNA conjugated NPs. (b) Delivery of miRNA‐146a loaded cerium oxide NPs using an injection in a swine excisional wound model showed decreased inflammation and increased angiogenesis. (c) Graphical representation showing application of NP mediated delivery of miR‐146a, its release and improvement in wound healing by means of decreased inflammation and increased angiogenesis. (d) Graphical representation showing nondiabetic wounds treated with PBS, diabetic wounds treated with PBS, and diabetic wounds treated with 100 ng CNP, 106 PFU LentimiR‐146a, or 100 ng of CNP‐miR‐146a at day 7 post‐wounding. (e) Representation of wound closure concerning the time of PBS and CNP‐miR‐146a treated wounds. The comparison was performed between PBS and CNP‐miR‐146a treated wounds. CNP, cerium oxide NPs; PBS, phosphate buffer saline. Parts (d) and (e) are reprinted from Reference with permission from Elsevier
FIGURE 8
FIGURE 8
Schematic representation of antihypoxamiR lipid NPs for cutaneous wound healing. (a) Schematic representation of the functionalization of AFGLN. (b) Delivery of AntimiR‐210 using AFGLN improved ischemic wound closure. (c) Digital photographs showing (i) murine ischemic wound at days 0, 2, 4, and 6 days after delivery of nascent GLN, AFGLN scramble, and AFGLNmiR‐210. (ii) Hematoxylin and eosin (H&E) stained sections from the ischemic wounds at day 6 post‐wounding. AFGLN, AntihypoxamiR functionalized gramicidin lipid NPs; GLN, gramicidin. Reprinted from Reference with permission from Elsevier
FIGURE 9
FIGURE 9
Schematic representation showing the preparation of Gel/Alg@ori/HA‐PEI@siRNA‐29a hydrogel and how siRNA‐29a loaded hydrogels accelerate the wound repair process. (a) Schematic representation of siRNA‐29a loaded hydrogels in wound healing and repair. (b) Digital photographs showing the process of healing on 0, 7, 10, 14, 21, and 24 days. (c) (i) Expression levels of α‐SMA, CD31, IL‐6, and TNF‐α using western blot techniques. (ii) Semiquantitative expression levels α‐SMA, CD31, IL‐6, and TNF‐α on day 7. Alg, alginate; Gel, Gelatin; HA, hyaluronic acid; Ori, oridonin; PEI, polyethyleneimine. Parts (b) and (c) are reprinted from Reference with permission from Elsevier
FIGURE 10
FIGURE 10
Schematic representation NP/miR‐223‐loaded gelatin methacryloyl hydrogels. Schematic illustration of the process involved in the synthesis of NA/miR‐233 loaded GelMA hydrogels and their application in wound healing
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