Fibroblast Activation Protein-Based Radio-Theranostics Attenuates Postinfarction Myocardial Fibrosis

Excessive fibrosis drives adverse remodeling after myocardial infarction (MI), yet targeted theranostic strategies remain limited. To enable precise diagnosis and intervention, we developed a FAP-dimer-based imaging/therapeutic platform using ⁶⁸Ga-DOTA-2P(FAPI)₂ for noninvasive visualization of fibroblast activation and its therapeutic analogue ¹⁷⁷Lu-DOTA-2P(FAPI)₂ for radionuclide therapy. Cardiac function and fibrosis progression were assessed by echocardiography and histopathology, biosafety was evaluated via serum biochemistry and organ staining, and single-cell RNA sequencing (scRNA-seq) was performed to elucidate the underlying mechanisms. ⁶⁸Ga-DOTA-2P(FAPI)₂ demonstrated a high and specific uptake in early post-MI fibrotic regions. Therapeutic administration of ¹⁷⁷Lu-DOTA-2P(FAPI)₂ at day 7 significantly reduced myocardial fibrosis and improved cardiac function in both short- and long-term (3 and 28 days) evaluations. No significant toxicity was observed within 7 days post-treatment. scRNA-seq revealed selective depletion of activated fibroblasts and suppression of pro-inflammatory signaling in the infarct border zone, confirming the antifibrotic mechanism.