D609-polymer-based delivery strategy targeting ferroptosis in treatment of dry eye disease

• D609 suppresses ferroptosis in HCECs by activating the NRF2-MT pathway. • PAA-CD-DA enhances D609 retention and penetration, improving DED treatment. • D609-loaded PAA-CD-DA protects the ocular surface in a DED mouse model. Dry eye disease (DED) affects about one-third of the global population, causing tear film instability and various ocular symptoms. Traditional treatments, including artificial tears and anti-inflammatory agents, offer symptom relief but can lead to adverse effects with long-term use. Recent research highlights oxidative stress and ferroptosis, a cell death process driven by iron accumulation, as key factors in DED. This study focuses on Tricyclodecan-9-yl xanthogenate (D609), a synthetic compound with diverse biological activities. D609 was tested for its ability to inhibit ferroptosis in corneal epithelial cells. Additionally, a new drug delivery system was developed by combining catechol and β-cyclodextrin with poly (acrylic acid) (PAA-CD-DA) to enhance ocular bioadhesion and drug penetration. Results showed D609 effectively inhibited ferroptosis, and the PAA-CD-DA carrier improved drug retention and corneal penetration. This dual-target approach shows promise for DED treatment, with further work needed to optimize the delivery system for clinical use.