My laboratory aims to develop new biotherapeutics for cardiac protection and cardiac repair after myocardial infarction. Over the last years, we have pursued the concept that cardiac regeneration can be achieved through the stimulation of endogenous cardiomyocyte proliferation and have identified a series of microRNAs that stimulate this process in both small and large animals. A challenge for the translation of these findings to patients is to identify a mode for non-coding RNA delivery that is suitable to clinical application. Expression of pro-proliferative small RNAs in cardiomyocytes using AAV vectors is highly efficient. However, transgene expression cannot be controlled and becomes deleterious over time. Transient administration of synthetic RNAs using cationic lipid-based lipoplexes is sufficient to restore cardiac function, but these molecules show an unacceptable safety profile due to their pro-inflammatory properties. Lipid nanoparticles (LNPs) based on the Stable Nucleic Acid Lipid Particles (SNALPs) technology have already reached clinical approval for siRNA administration with patisiran in 2018 and have shown remarkable efficacy in the COVID-19 vaccines by Pfizer-BioNTech and Moderna for mRNA delivery recently. Different LNP formulation carrying the pro-regenerative miRNA-199a-3p in both mice and pigs are effective at stimulating cardiomyocyte proliferation, are maintained in the heart for over 10 days in an active form and are sufficient to stimulate functional cardiac repair. Further improvements can be achieved by including chemical modifications in the miRNA backbone to extend stability over time. One of the tested miR-199-SNALPs (LNP199) is our current lead formulation for clinical development.