Virus-inspired nanozymes for two-dimensional biomimetic penetration and long-acting ferroptosis inhibition in treating dry eye disease.

Dry eye disease (DED) has become a global health concern impacting approximately 1.487 billion individuals, yet it remains unresolved. Ferroptosis, a form of non-apoptotic corneal epithelial cell death, has recently emerged as a significant focus in the therapeutic management of DED. However, owing to the corneal epithelial barrier and oxidative stress-inflammation crosstalk, no therapeutic strategy can precisely and sustainably inhibit ferroptosis in DED. This study pioneers a transformative paradigm in DED therapy by ingeniously fusing a virus-like hollow mesoporous cerium oxide nanozyme (vHMCe) core-loaded with cyclosporin A (CsA) and surface-functionalized with rabies virus glycoprotein 29 (RVG29) to achieve long-acting ferroptosis inhibition in DED treatment. Structurally, CsA@vHMCe-RVG mimicks the roughness and irregularity of viral surfaces, endowing spike-assisted adhesion to corneal epithelial cells. Functionally, RVG interacts with nicotinic acetylcholine receptors (nAChRs), triggering receptor-mediated transmembrane transport for efficient internalization. The cerium valence cycle and CsA can synergistically block oxidative stress-inflammation interactions to achieve long-acting ferroptosis inhibition in DED. CsA@vHMCe-RVG attains scavenging rates of 95 % and 90 % for intracellular reactive oxygen species and ferroptosis levels in corneal epithelial cells under continuous hydrogen peroxide stimulation four times. The integration of biomimetic transmembrane effects and ferroptosis inhibition offers an innovative strategy with significant clinical application potential for DED treatment.