Intrapericardial delivery of FAP-CAR-T cells via a ROS-responsive hydrogel to treat cardiac fibrosis

Cardiac fibrosis is a key pathological feature of both acute and chronic heart diseases, characterized by abnormal accumulation of extracellular matrix resulting from fibroblast activation. Although fibroblast activation protein (FAP)-targeted chimeric antigen receptor (CAR) T cell therapy has shown promise in selectively eliminating activated fibroblasts, systemic administration remains limited by off-target toxicity and insufficient trafficking to the diseased myocardium. Here, we present a reactive oxygen species (ROS)-responsive hydrogel designed for intrapericardial delivery of FAP-specific CAR-T (FAP-CAR-T) cells to locally treat post-myocardial infarction (MI) fibrosis. This hydrogel, based on a thioketal-crosslinked polyethylene glycol matrix, selectively degrades in the ROS-enriched microenvironment of fibrotic tissue, enabling the controlled release of encapsulated FAP-CAR-T cells. In vitro, FAP-CAR-T cells exhibited antigen-dependent cytotoxicity against FAP⁺ targets, and hydrogel-encapsulated CAR-T cells maintained robust proliferation and showed ROS-triggered release kinetics. Using murine models of MI-induced fibrosis, the hydrogel-based intrapericardial delivery strategy enhanced FAP-CAR-T cells infiltration, persistence, and effector function, resulting in significant depletion of activated fibroblasts, attenuation of fibrotic remodeling, and preservation of cardiac structure and left ventricular function. This hydrogel-based CAR-T immunotherapeutic platform provides a localized, targeted, and on-demand strategy for combating cardiac fibrosis and may offer broader translational potential for the treatment of fibrotic diseases.