Matrices Activated with Messenger RNA

Abstract

Over two decades of preclinical and clinical experience have confirmed that gene therapy-activated matrices are potent tools for sustained gene modulation at the implantation area. Matrices activated with messenger RNA (mRNA) are the latest development in the area, and they promise an ideal combination of efficiency and safety. Indeed, implanted mRNA-activated matrices allow a sustained delivery of mRNA and the continuous production of therapeutic proteins in situ. In addition, they are particularly interesting to generate proteins acting on intracellular targets, as the translated protein can directly exert its therapeutic function. Still, mRNA-activated matrices are incipient technologies with a limited number of published records, and much is still to be understood before their successful implementation. Indeed, the design parameters of mRNA-activated matrices are crucial for their performance, as they affect mRNA stability, device immunogenicity, translation efficiency, and the duration of the therapy. Critical design factors include matrix composition and its mesh size, mRNA chemical modification and sequence, and the characteristics of the nanocarriers used for mRNA delivery. This review aims to provide some background relevant to these technologies and to summarize both the design space for mRNA-activated matrices and the current knowledge regarding their pharmaceutical performance. Furthermore, we will discuss potential applications of mRNA-activated matrices, mainly focusing on tissue engineering and immunomodulation.

Gelatin methacryloyl granular scaffolds for localized mRNA delivery

“…[17] In addition, some systemic transfection limitations, such as nonprolonged delivery of the transgene and the non-confined and localized effect of its overexpression, could be overcome by combining 3D hydrogel-based matrices or scaffolds with gene delivery, in particular mRNA delivery. [18][19][20][21] In tissue engineering, traditional "bulk" hydrogels, produced via conventional techniques, have some limitations over specific applications, particularly when an injection or smaller sizes are required. As an alternative to traditional bulk hydrogels, small-scale gels have stood out with several unique properties that make them attractive for biomedical applications.…”

“…Even though mRNA-releasing matrices are emerging technologies, their application is still scarce in the literature, requiring further study to be applied clinically. [18,21] Herein, we reported, for the first time, a microporous gelatin methacryloyl (GelMA) scaffold for the transgene expression of mRNA. GelMA MAP scaffolds have already been shown to be suitable for cell adhesion, migration, and proliferation.…”

“…[ 17 ] In addition, some systemic transfection limitations, such as non‐prolonged delivery of the transgene and the non‐confined and localized effect of its overexpression, could be overcome by combining 3D hydrogel‐based matrices or scaffolds with gene delivery, in particular mRNA delivery. [ 18–21 ]…”

“…Even though mRNA‐releasing matrices are emerging technologies, their application is still scarce in the literature, requiring further study to be applied clinically. [ 18,21 ]…”