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WIREs Nanomed Nanobiotechnol
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Nanoparticle mediated RNA delivery for wound healing

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Abstract Wound healing is a complicated physiological process that comprises various steps, including hemostasis, inflammation, proliferation, and remodeling. The wound healing process is significantly affected by coexisting disease states such as diabetes, immunosuppression, or vascular disease. It can also be impacted by age, repeated injury, or hypertrophic scarring. These comorbidities can affect the rate of wound closure, the quality of wound closure, and tissues' function at the affected sites. There are limited options to improve the rate or quality of wound healing, creating a significant unmet need. Advances in nucleic acid research and the human genome project have developed potential novel approaches to address these outstanding requirements. In particular, the use of microRNA, short hairpin RNA, and silencing RNA is unique in their abilities as key regulators within the physiologic machinery of the cell. Although this innovative therapeutic approach using ribonucleic acid (RNA) is an attractive approach, the application as a therapeutic remains a challenge due to site‐specific delivery, off‐target effects, and RNA degradation obstacles. An ideal delivery system is essential for successful gene delivery. An ideal delivery system should result in high bioactivity, inhibit rapid dilution, controlled release, allow specific activation timings facilitating physiological stability, and minimize multiple dosages. Currently, these goals can be achieved by inorganic nanoparticle (NP) (e.g., cerium oxide, gold, silica, etc.) based delivery systems. This review focuses on providing insight into the preeminent research carried out on various RNAs and their delivery through NPs for effective wound healing. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology‐Inspired Nanomaterials > Nucleic Acid‐Based Structures
Schematic diagram for the biogenesis of microRNA (miRNA) molecules. A pri‐miRNA molecule forms a hairpin structure and is modified by DGCR8 and DROSHA to produce pre‐miRNA. The nucleus exports the pre‐miRNA molecule using Exportin‐5 and then matures using Dicer. Followed by miRNA duplex remains unwound. Moreover, the mature strand resides within the miRISC complex which subsequently fosters attachment to the 3′ untranslated region of mRNA or translational repression
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Schematic diagram of the different wound healing phases (a) normal skin, (b) hemostasis involves the promotion of platelets and formation of clots, (c) inflammation recruits leukocytes to wound site in order to release cytokines, (d) proliferation phase involves angiogenesis and extracellular matrix production, and (e) remodeling phase involves the organization and contraction of the extracellular matrix
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Research on microRNA (miRNA) delivery, wound healing, and wound care market value worldwide: (a) Three‐dimensional (3D) pie chart showed chronic diabetes, pressure, venous, and arterial wound care market values in the United States. (b) Bar graph showing the number of research publications per 2 years in the field of “miRNA delivery” (red bar) and “wound healing” (blue bar), both fields have received increasing interest from the broader scientific community (publication's data were retrieved from the web of science, clarivate analytics)
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Schematic illustration of microRNA (miRNA) conjugation with colloidal nanoparticles or biomolecules using chemical crosslinker of N,N′‐carbonyldiimidazole (CDI). (a) Chemical reaction scheme of the excess of hydroxyl group molecules conjugated with amine‐terminated miRNA molecules by carbamate linkage using CDI linker, (b) cerium oxide (CNPs) nanoparticles conjugated with amine‐terminated miRNA using CDI linker (Zgheib et al., 2019) and (c) two different miRNA molecules were conjugated on gold nanoparticles using heterofunctional crosslinker of sulfo‐GMBS and thiol group modified single‐stranded deoxyribonucleic acid (ssDNA). The miR was released by Au nanoparticles at the targeted site by modifying the energy output of the single‐pulse laser. (c(i)) Primarily, the succinimide ester group in sulfo‐GMBS crosslinker reacted with excess amine group‐containing miRNAs (miR‐302a or miR‐155). Subsequently, terminal thiol group‐containing ssDNA reacted with miR conjugate molecules to form a miR‐ssDNA. (c(ii)) Another ssDNA molecules connected with gold nanoparticles (AuNPs) to produce the AuNPs‐ssDNA. Finally, both miR‐ssDNA and AuNPs‐ssDNA complex were attached to produce AuNPs‐dsDNA (double‐stranded DNA)‐miR complex by hybridization technique. 2 kDa thiol‐PEG was used to cover the surface of AuNPs. Near‐infrared (NIR) ray irradiation causes an increase in heat at the AuNPs‐dsDNA‐miR complex, leading to dehybridization of DNA and the dispersion of miRs at various rates. The miR discharge rate depends on the NIR laser's power and oligonucleotides melting temperature (Wang, Kim, Kwak et al., 2020)
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Schematic diagram illustrates the miR‐CNPs incorporated collagen/gelatin scaffold preparation and how it promotes angiogenesis and tissue regeneration on the diabetic wound. The polyethyleneimine (PEI, molecular weight‐25 kDa) functionalized CNPs conjugated to miR‐26a by bioconjugation method. Furthermore, miR‐CNPs conjugated nanoparticles incorporated into collagen/gelatin hydrogel composites to fabricate a 3D miR‐CNPs/collagen/gelatin scaffold. The composite releases miR‐CNPs in a controlled manner and it promotes tissue growth when implanted in the diabetic wound surface. Controlled and continuous supplies of miR and CNPs from hydrogel composites promote fresh blood vessels formation and accelerate the new tissue formation at the site of diabetic wounds
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Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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