Smart Nanodelivery for Eye‐Brain Disorders: Synergistic CCL2 Neutralization and MMP9 Silencing Reverse Anxiety in High Myopia

ABSTRACT High myopia (HM), a major cause of global blindness, also significantly elevates anxiety risk via a newly discovered eye‐brain inflammatory axis. We identified C‐C motif chemokine ligand 2 (CCL2) as the key driver: HM visual stimuli trigger retinal CCL2 upsurge, promoting monocyte/macrophage infiltration into eyes and brain, disrupting blood‐brain (BBB) and blood‐ocular (BOB) barriers, and inducing anxiety. To shatter this vicious cycle, unmet by traditional CCL2 blockers (poor targeting, non‐selectivity, no barrier repair), we engineered a revolutionary ROS‐responsive nanocomplex, TK‐F‐PEI/siR@A. This system synergistically integrates: (1) Surface CCL2 aptamers for targeted lesion homing and CCL2 neutralization; (2) A fluorinated, thioketal‐crosslinked low‐MW PEI core enabling inflammation‐triggered release; (3) Encapsulated MMP9 siRNA to restore barrier integrity. TK‐F‐PEI/siR@A demonstrated excellent ROS responsiveness, low cytotoxicity, and effective MMP9 silencing, enhancing tight junctions. Guided by aptamers, it achieved superior accumulation in inflamed ocular/brain regions of HM mice, with high biosafety. Critically, it delivered a dual‐action strike: significantly reducing CCL2 levels, suppressing systemic/local monocyte/macrophage infiltration, and robustly repairing BBB/BOB integrity. This synergistic blockade of inflammation and barrier restoration reversed anxiety‐like behaviors. We pioneer the first nanocomplex specifically co‐targeting the eye‐brain axis, establishing a potent dual‐pronged strategy against HM‐related anxiety and offering a new paradigm for inter‐organ crosstalk disorders.