Polyphenol-Loaded Nanodevices as Innovative Therapeutic Strategies for Dry Eye Disease: Advances and Perspectives.

Background: Dry Eye Disease (DED) is a multifactorial ocular disorder characterized by tear film instability, inflammation, oxidative stress, and ocular surface damage. Current therapeutic options often provide only temporary relief and are limited by poor patient compliance and inadequate drug retention at the ocular surface. Aim: This review aims to critically analyze the therapeutic potential of polyphenols and their nanoencapsulated formulations for the management of DED, focusing on pharmacological mechanisms, formulation strategies, and translational implications. Methods: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science databases using combinations of the following keywords: "dry eye disease," "polyphenols," "antioxidants," "nanocarriers," "ocular delivery," and "bioavailability." Studies published in English from 2000 to 2024 were considered. Inclusion criteria encompassed experimental, preclinical, and clinical studies evaluating polyphenol-based formulations for ocular application, while reviews without original data or studies unrelated to DED were excluded. Results: The analysis identified EGCG, curcumin, resveratrol, and quercetin as the most extensively investigated polyphenols, exhibiting antioxidant, anti-inflammatory, and cytoprotective activities through modulation of cytokines, reactive oxygen species, and immune signaling pathways. Nanoformulations such as lipid nanoparticles, micelles, and cyclodextrin complexes improved solubility, stability, ocular retention, and bioavailability, leading to enhanced therapeutic efficacy in preclinical DED models. Conclusions and Future Perspectives: Polyphenol-loaded nanocarriers represent a promising approach for improving the management of DED by enhancing local drug delivery and sustained release. However, further clinical studies are needed to assess long-term safety, scalability, and regulatory feasibility. Future research should focus on optimizing formulation reproducibility and exploring personalized nanotherapeutic strategies to overcome interindividual variability in treatment response.