Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin 2228-5881 14 3 2024 10 10 Novel Advances in Cell-Free Therapy for Premature Ovarian Failure (POF): A Comprehensive Review 543 557 10.34172/apb.2024.059 EN Yahya Yahyavi https://orcid.org/0000-0001-9169-8245 Niloufar Kheradi https://orcid.org/0009-0002-4872-4414 Abbas Karimi https://orcid.org/0000-0002-1172-8502 Abbas Ebrahimi-Kalan https://orcid.org/0000-0001-5466-6754 Fatemeh Ramezani https://orcid.org/0000-0002-0127-6012 Soudabe Yousefi https://orcid.org/0000-0001-5668-2248 Shirin Teymouri Nobari https://orcid.org/0000-0003-2714-6141 Hourieh Sadrekarimi https://orcid.org/0000-0006-9949-8671 Mohammad Nouri https://orcid.org/0000-0002-5367-9956 Mahdi Edalati https://orcid.org/0000-0001-8284-348X REVIEW 10.34172/apb.2024.059 2024 02 19 2024 07 30 Premature ovarian failure (POF), is a condition characterized by the early decline of ovulation function. POF is a complex disorder that can be caused by various factors, and the idiopathic form represents a significant proportion of POF patients. Hormone replacement therapy (HRT) is currently considered the first-line treatment for POF. This review aims to provide a comprehensive overview of recent advancements in platelet-rich plasma (PRP), in vitro activation (IVA), stem cell therapy, exosome therapy, microRNAs, and mitochondrial targeting therapies as a promising cell-free therapeutic approach in reproductive medicine. PLT-Exos, a new generation of cells, has been used to treat POF for more than a decade and has been shown to attenuate oocyte morphology and promote the differentiation of theca cells through the upregulation of PI3K/Akt and Bcl2, as well as the downregulation of the Smad and Bax signaling pathways. This review summarizes the current state of the art in the field of PLT-Exos and discusses the advantages and limitations of their potential clinical applications.