mRNA-activated matrices encoding transcription factors as primers of cell differentiation in tissue engineering

Hydrogel-Based Localized Nonviral Gene Delivery in Regenerative Medicine Approaches—An Overview

“…In contrast to siRNA being focused on downregulation of intracellular mechanisms, hydrogel-mediated mRNA controlled delivery is primarily intended to promote tissue formation or certain aspects of cellular response, such as differentiation, reprogramming, and protein secretion [3]. By these lines, a GAM based on fibrin-based hydrogel activated with mRNAs encoding for transcription factors (TF) SOX9 (cartilage) and MYOD (muscle) and loaded with hMSCs was developed [17]. Results from this study showed a higher and faster TF expression in hMSCs when using mRNA-GAMs as compared with pDNA-GAMs, resulting in enhanced synthesis of cartilage and muscle-specific markers in vitro.…”

“…Unlike to pDNA, mRNA does not need to enter in the cell nucleus to be functional, requiring only the translational machinery in the cytosol for expression of its protein product [16]. Therefore, a superior gene transfer efficiency has been reported for mRNA molecules compared with pDNA [17]. However, a higher instability and host immunogenicity have been reported for mRNA molecules [18].…”

“…Likewise, in an effort to control the release kinetics and preserve the activity of therapeutic biomolecules, hydrogels have been widely investigated as gene delivery systems [ 15 ]. Various hydrogels systems based on natural polymers such as alginate [ 33 , 34 , 35 , 36 , 37 , 38 , 39 ]; cellulose [ 40 ]; chitosan [ 41 , 42 , 43 , 44 ] ( Table 1 ); collagen [ 45 , 46 , 47 ]; dextran [ 48 ]; fibrin [ 17 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ]; pullulan [ 56 ] ( Table 1 ); gelatin [ 57 , 58 , 59 , 60 ]; hyaluronic acid (HA) [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ] ( Table 1 ); or synthetic ones as polyethylene-glycol (PEG) [ 70 , 71 , 72 , 73 ,…”

“…Similarly, controlled delivery of RNA molecules from hydrogels networks may enhance local and sustained siRNA [ 43 , 44 , 48 , 49 , 56 , 59 , 71 , 75 , 76 , 78 , 79 , 85 , 86 ] and miRNA [ 46 , 47 , 60 , 62 , 63 , 80 , 81 , 82 , 84 , 92 ] delivery limiting undesired targets [ 14 ], and protect mRNA nanoparticles from the biological environment improving their cellular access [ 17 , 58 ].…”

Scaffold-Mediated Gene Delivery for Osteochondral Repair

“…In vitro assays showed long-term transgene expression, prompting MSCs differentiation into osteogenic and chondrogenic lineages [ 121 ]. Recently, a fibrin-based hydrogel activated with an mRNA coding for the transcription factor SOX9 was reported to promote MSC chondrogenesis in vitro, with improved expression of sox9 in progenitor cells compared with the administration of hydrogels activated with pDNA encoding for this transcription factor [ 122 ]. Similarly, micro-macro biphasic calcium phosphate (MBCP) granules activated with an mRNA for BMP-2 were described for their ability to support MSC osteogenic differentiation with triggered higher expression of type-I collagen and osteocalcin relative to the use of activated fibrin hydrogels [ 123 ].…”