Lipid Nanoparticle-Mediated mRNA Delivery to the Heart: From Bench to Preclinical Models

This thesis investigates the potential of lipid nanoparticles (LNPs) as delivery vehicles for modified messenger RNA (modRNA) in the treatment of heart disease, with a particular focus on myocardial infarction (MI). This research work began in April 2020, at the very onset of the COVID-19 pandemic. In parallel with the first steps of this project, the world witnessed the first clinical approval of modRNA–LNP-based drugs with the rapid development of modRNA vaccines against SARS-CoV-2. This unprecedented moment marked a turning point in LNP drug development, demonstrating the transformative power of LNP-mediated nucleic acid delivery. At the same time, it positioned LNP technology as one of the most relevant and fast-evolving fields in modern biomedical research.
Heart failure remains one of the leading causes of death worldwide, and despite major advances in cardiovascular medicine, there are still no therapies that can restore diseased cardiac tissue to its normal function. Myocardial infarction, the most common cause of heart failure, results from the obstruction of a coronary artery, leading to ischemia, cardiomyocyte death, and ultimately the formation of non-contractile scar tissue. Because the adult heart has extremely limited regenerative capacity, the loss of functional myocardium leads to chronic pathological remodelling and progressive heart failure. For patients with end-stage disease, heart transplantation remains the only curative option, but organ scarcity and poor prognosis underscore the urgent need for innovative therapeutic strategies.
Messenger RNA therapeutics have emerged as a promising approach to address this challenge. By providing transient expression of therapeutic proteins directly within cardiac cells, modRNA has the potential to promote cardiomyocyte survival, stimulate angiogenesis, and even support regeneration. The major hurdle, however, lies in the safe and efficient delivery of RNA to the heart. Naked RNA molecules are inherently unstable, rapidly degraded in the extracellular environment, and poorly taken up by cells. Lipid nanoparticles offer a solution to these challenges: they protect RNA cargo, facilitate cellular uptake, and improve intracellular release, thereby enabling RNA molecules to reach their site of action.
In line with this, the studies presented in the thesis show that LNP-mediated delivery is highly more effective requiring dramatically lower doses of modRNA to achieve high levels of protein expression compared to conventional buffer-based administration. By comparing experimental and clinically approved formulations, this thesis explores how variations on the LNP´s lipid composition influence their performance in delivering modRNA to the heart.However, a major challenge that emerged was the marked immune cell infiltration induced by the locally injected LNPs, highlighting the need for strategies to mitigate these immune responses in future therapeutic development.
Altogether, the findings of this thesis demonstrate that LNPs can serve as powerful vectors for cardiac modRNA delivery, overcoming key barriers that have historically limited nucleic acid therapeutics in the heart. They show that the design of the lipid formulation is crucial for balancing efficacy, safety, and biodistribution, and they highlight strategies to further enhance delivery efficiency. Taken together, this work contributes to the growing amount of evidence that mRNA-LNP platforms hold transformative potential for treating cardiovascular disease.