FAP-targeted gastrodin nanoparticles in responsive hydrogel alleviate cardiac fibrosis via fibroblast metabolic reprogramming

Ischemic heart disease, particularly myocardial infarction (MI), is a leading cause of global mortality, and the resulting myocardial fibrosis significantly impairs cardiac function, contributing to heart failure. Despite considerable efforts, effective therapeutic interventions for reversing myocardial fibrosis and restoring heart function remain elusive. Recent studies highlight the crucial role of metabolic reprogramming in the activation of cardiac fibroblasts (CFs) and their transformation into myofibroblasts, which drive fibrosis. Gastrodin (GAS), a phenolic glycoside derived from Gastrodia elata , has demonstrated promising anti-fibrotic and metabolic regulatory effects; however, its clinical application has been limited by poor pharmacokinetic properties and lack of targeted delivery. Here, we designed an intrapericardial (iPC) injection nanocomposite hydrogel incorporating FAP-targeted CAR-T cell membrane-coated GAS nanoparticles (FAP-CAR T CM@PPA-G NPs) within a pH/ROS-responsive CP/PCPD hydrogel. This innovative system achieves specific targeting of FAP-positive myofibroblasts, on-demand release of GAS triggered by pathological ROS and pH changes, and effective inhibition of fibrosis by modulating the KLF2/CREB5/HIF-1α/PFKFB3 metabolic axis. Our findings not only provide a novel therapeutic platform for post-MI fibrosis treatment but also elucidate the mechanistic basis of GAS's anti-fibrotic effects. This strategy offers significant promise for advancing the clinical translation of GAS-based therapies for myocardial fibrosis and heart failure. Construction and mechanism of the FAP-CAR T CM@PPA-G nanoparticle composite hydrogel in regulating glycolysis and inhibiting myocardial fibrosis. 1) Gene-engineer Jurkat T cells to stably express the FAP single-chain antibody, and isolate FAP-CAR T cell membrane vesicles (FAP-CAR T CM) using the freeze-thaw method. Gastrodin is then grafted onto Phenylboronic acid-functionalized poly (citric acid ester) nanoparticles (PPA) using an emulsification-dispersion method to form PPA-G nanoparticles. The FAP-CAR T CM and PPA-G nanoparticles are co-extruded to generate the FAP-CAR T CM@PPA-G nanoparticle complex. 2) The FAP-CAR T CM@PPA-G nanoparticles are mixed with the CP/PCPD hydrogel and injected into the pericardial cavity of mice with MI. 3) The FAP-CAR T CM@PPA-G nanoparticles specifically target activated fibroblasts, reducing their glycolysis activity, and thus inhibiting their fibrotic phenotype. This nanoparticle system effectively reduces myocardial fibrosis and improves cardiac function in MI models. • Developed a dual pH/ROS-responsive FAP-targeted nanocomposite hydrogel for intrapericardial gastrodin delivery. • FAP-CAR T cell membrane camouflage enables precise targeting of activated cardiac fibroblasts. • The nanoplatform suppresses fibroblast activation via the KLF2/CREB5/HIF-1α/PFKFB3 glycolytic pathway. • The system alleviates post-MI myocardial fibrosis and improves cardiac function.