<![CDATA[Dry Eye Disease (DED) is a multifactorial ocular surface disorder characterized by tear film instability and chronic inflammation, resulting in discomfort and visual disturbance. Conventional treatments such as artificial tears and anti-inflammatory agents mainly provide symptomatic relief and show limited regenerative potential. Secretome-based therapy, derived from mesenchymal stem cells (MSCs), has recently emerged as a promising cell-free regenerative approach. This systematic review aims to evaluate the efficacy, safety, and mechanisms of topical secretome therapy for DED in animal models. A systematic literature search was conducted in PubMed, Google Scholar, and ScienceDirect for studies published between January 2004 and August 2025. Eligible studies included animal models of DED treated with MSC-derived secretome, exosomes, or conditioned medium administered as topical eye drops. Data extraction followed PRISMA guidelines, and study quality was assessed using the SYRCLE’s risk of bias tool for animal research. Eleven animal studies met the inclusion criteria. Topical secretome therapy significantly improved tear break-up time and tear production in most studies and reduced corneal fluorescein staining, indicating enhanced tear film stability and epithelial repair. Histological analyses revealed increased goblet cell density, reduced inflammatory cytokines, and decreased apoptosis markers. No ocular or systemic adverse effects were reported, confirming good tolerability across all animal models. Topical secretome therapy demonstrates strong anti-inflammatory, anti-apoptotic, and regenerative effects in animal models of DED, with a favorable safety profile. Future research should focus on standardizing secretome production and conducting clinical studies to confirm its translational potential as cell-free therapy for ocular surface regeneration. ]]>
