Gelatin methacryloyl granular scaffolds for localized mRNA delivery

Messenger RNA (mRNA) therapy is the intracellular delivery of mRNA to produce desired therapeutic proteins. Developing strategies for local mRNA delivery is still required where direct intra-articular injections are inappropriate for targeting a specific tissue. The mRNA delivery efficiency depends on protecting nucleic acids against nuclease-mediated degradation and safe site-specific intracellular delivery. Herein, novel mRNA-releasing matrices based on RGD-moiety-rich gelatin methacryloyl (GelMA) microporous annealed particle (MAP) scaffolds are reported. GelMA concentration in aerogel-based microgels (mu gels) produced through a microfluidic process, MAP stiffnesses, and microporosity are crucial parameters for cell adhesion, spreading, and proliferation. After being loaded with mRNA complexes, MAP scaffolds composed of 10% GelMA mu gels display excellent cell viability with increasing cell infiltration, adhesion, proliferation, and gene transfer. The intracellular delivery is achieved by the sustained release of mRNA complexes from MAP scaffolds and cell adhesion on mRNA-releasing scaffolds. These findings highlight that hybrid systems can achieve efficient protein expression by delivering mRNA complexes, making them promising mRNA-releasing biomaterials for tissue engineering. Discover a novel approach for localized messenger RNA (mRNA) delivery through gelatin methacryloyl microporous annealed particle scaffolds. The sustained release of mRNA complexes achieves indirect intracellular delivery. In contrast, direct intracellular delivery is achieved by cell adhesion on mRNA-releasing scaffolds. Witness a hybrid system achieving efficient protein expression, offering the potential for mRNA-releasing biomaterials for tissue engineering.image