Fibroblast Activation Protein α Targeted Nanomaterial-Mediated Sonodynamic Therapy for Myocardial Fibrosis Reversal

One of the most severe and fatal cardiovascular conditions is myocardial infarction (MI). Following MI, a significant proportion of cardiac fibroblasts (CFs) become activated. The effective modulation of CFs’ function post-MI is essential for reducing fibrosis and enhancing cardiac function. Sonodynamic therapy (SDT) represents a noninvasive therapeutic approach that has been used extensively in oncology treatment but has not been studied in myocardial fibrosis. Therefore, we developed and synthesized a lipid nanoparticle encapsulating 5-aminolevulinic acid (5-ALA) and modified its surface with a fibroblast activation protein α (FAP-α) inhibitor to explore the therapeutic potential and underlying mechanisms of FAP-α-targeted nanomaterial-mediated sonodynamic therapy in conjunction with the delivery of 5-ALA for reversing myocardial fibrosis. This FAP-α/ultrasound dual-targeted nanoparticle represents the first integration of SDT with FAP-α-targeted treatment aimed at reversing myocardial fibrosis. Additionally, it elucidates, for the first time, the crucial regulatory role of GSK-3α, as opposed to glycogen synthase kinase-3β (GSK-3β), in the antifibrotic effects mediated by SDT.