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

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.