Quercetin-loaded exosomes delivery system prevents myopia progression by targeting endoplasmic reticulum stress and ferroptosis in scleral fibroblasts

Myopia, a predominant cause of visual impairment, is often associated with scleral extracellular matrix (ECM) remodeling and axial elongation. Currently, effective therapeutic strategies for addressing scleral ECM remodeling remain limited, necessitating the development of new treatments. Quercetin, a natural flavonoid, has been shown to alleviate ECM remodeling. However, its hydrophobic nature limits clinical application. To address this, we developed a quercetin-loaded exosome delivery system (Exo-Que) to enhance quercetin bioavailability and investigated its effects and mechanisms in myopia prevention. This system exhibited excellent aqueous solubility, enhanced corneal permeability, and prolonged precorneal retention, enabling low-dose administration with significant efficacy. In the initial phase of treatment, Exo-Que showed a pronounced myopia prevention effect, with reductions of 58.41 % in refractive error progression and 38.46 % in axial length growth after two weeks of treatment. As the treatment duration extended to four weeks, its therapeutic efficacy remained robust, achieving reductions of 59.97 % and 35.85 %, respectively. The therapeutic efficacy of Exo-Que was comparable to that of the 0.1 % atropine group (at two weeks, reducing 59.07 % and 35.9 %, respectively; at four weeks, 59.84 % and 37.74 %, respectively). Mechanistically, Exo-Que inhibited the activation of the IRE1-XBP1, PERK-eIF2, and ATF6 pathways, alleviating endoplasmic reticulum stress. Furthermore, it suppressed ferroptosis by modulating GRP78-ACSL4 and GRP78-GPX4 protein interactions, thus mitigating ECM remodeling and slowing myopia progression. Besides, Exo-Que showed excellent biosafety in both <i>in vitro</i> and <i>in vivo</i> studies. Collectively, these results highlight the promising therapeutic potential of Exo-Que for myopia prevention.