Heart failure (HF) is characterized by inflammation and a progressive fibrosis reducing the pumping efficiency of the heart. Inflammatory cells (ICs) and cardiac fibroblasts (CFs) are involved in myocardial fibrosis by a biphasic secretion of pro/anti-inflammatory cytokines and differentiation into ‘myofibroblats’, respectively. This leads to abundant collagen deposition with an increase in extracellular matrix (ECM) stiffness and a reduced contractility.

The changes in the ECM characteristics also determine compensatory modifications of the cardiomyocytes (CMs) contractile apparatus and eccentric or concentric hypertrophy. This project is based on still unexplored approach to treat myocardial fibrosis with molecular tools interfering with intracellular transduction of mechanical forces valorizing the finding that ICs, CFs and CMs respond to tissue mechanics such as the stiffness and/or the strain of the surrounding matrix. Corroborated by robust preliminary results and a solid conceptual framework, Nano-to-Heart Consortium will target the function of the principal mechanically-activated pathways (e.g., the YAP/TAZ, Hippo transcriptional machinery) in ICs and CFs with selective delivery of ‘theranostic’ nanoparticles (NPs) containing a YAP/TAZ targeting drug or interfering oligonucleotides, after coating with hyaluronic acid (HA), a high affinity ligand for CD44 expressed in these cells.

The NPs will be synthesized using materials complying with GLP/GMP and FDA/EMA standards and will be tested in vitro using available/novel 3D cardiac fibrosis models and in vivo models (zebrafish and mouse models). The NPs will be tested for toxic effects on endothelial cells (ECs) and on ECs/ICs interactions under dynamic flow conditioning in a microfluidics platform. To assess non-invasive homing NPs will contain contrast agents or photoacoustic probes suitable for imaging systems such as cardiac magnetic resonance imaging (MRI) or echocardiography.