Injectable hydrogel with MSNs/microRNA-21-5p delivery enables both immunomodification and enhanced angiogenesis for myocardial infarction therapy in pigs

Abstract

On-demand controlled miR-21-5p delivery system integrates immune modification and proangiogenesis assists MI therapy. Current therapeutic strategies such as angiogenic therapy and anti-inflammatory therapy for treating myocardial infarction have limited success. An effective approach may benefit from resolution of excessive inflammation combined with enhancement of angiogenesis. Here, we developed a microRNA-21-5p delivery system using functionalized mesoporous silica nanoparticles (MSNs) with additional intrinsic therapeutic effects. These nanocarriers were encapsulated into an injectable hydrogel matrix (Gel@MSN/miR-21-5p) to enable controlled on-demand microRNA-21 delivery triggered by the local acidic microenvironment. In a porcine model of myocardial infarction, we demonstrated that the released MSN complexes notably inhibited the inflammatory response by inhibiting the polarization of M1 macrophage within the infarcted myocardium, while further microRNA-21-5p delivery by MSNs to endothelial cells markedly promoted local neovascularization and rescued at-risk cardiomyocytes. The synergy of anti-inflammatory and proangiogenic effects effectively reduced infarct size in a porcine model of myocardial infarction.