Trophoblast stem cells (TSCs) have been confirmed to play a cardioprotective role in
heart failure. However, whether
TSC-derived exosomes (
TSC-exos) can protect against cardiac injury remains unclear. In the present study,
TSC-exos were isolated from the supernatant of TSCs using the ultracentrifugation method and characterized by transmission electron microscopy and western blotting. Utilizing the public Gene Expression Omnibus (GEO) database, we found that let-7i and Yes-associated
protein 1 (YAP) could participate in the development of
heart failure. In vitro, AC16 cardiomyocytes subjected to
doxorubicin (DOX) were treated with
TSC-exos or let-7i mimic. Flow cytometry showed that
TSC-exos and let-7i both decreased cardiomyocyte apoptosis. In vivo, mice that were intraperitoneally injected into DOX received either PBS,
TSC-exos, or AAV9-let7iup for let-7i overexpression. Mice receiving
TSC-exos and AAV9-let7iup showed improved cardiac function and decreased inflammatory responses, accompanied by downregulated YAP signaling. Mechanistically,
TSC-exos could transfer let-7i to cardiomyocytes and silence the YAP signaling pathway. In conclusion,
TSC-exos could alleviate DOX-induced cardiac injury via the let-7i/YAP pathway, which sheds new light on the application of
TSC-exos as a potential therapeutic tool for
heart failure.