Smart Nanodelivery for Eye-Brain Disorders: Synergistic CCL2 Neutralization and MMP9 Silencing Reverse Anxiety in...

Area of Science:

• Ophthalmology and Neuroscience
• Biomaterials and Nanotechnology

Background:

• High myopia (HM) is a leading cause of blindness and is linked to increased anxiety risk.
• A newly discovered eye-brain inflammatory axis, driven by C-C motif chemokine ligand 2 (CCL2), mediates this connection.
• CCL2 triggers inflammation, disrupts blood-brain (BBB) and blood-ocular (BOB) barriers, and promotes anxiety.

Purpose of the Study:

• To develop a novel therapeutic strategy to counteract the HM-induced eye-brain inflammatory axis and associated anxiety.
• To engineer a targeted, inflammation-responsive nanocomplex for simultaneous CCL2 neutralization and barrier repair.

Main Methods:

• Development of a ROS-responsive nanocomplex (TK-F-PEI/siR@A) integrating CCL2 aptamers, a fluorinated PEI core, and MMP9 siRNA.
• In vitro assessment of ROS responsiveness, cytotoxicity, and MMP9 silencing efficacy.
• In vivo evaluation in HM mice, assessing targeted delivery, BBB/BOB integrity repair, inflammation reduction, and behavioral changes.

Main Results:

• The nanocomplex demonstrated excellent ROS responsiveness, low cytotoxicity, and effective MMP9 silencing, enhancing tight junctions.
• TK-F-PEI/siR@A achieved targeted accumulation in inflamed ocular and brain regions with high biosafety.
• The treatment significantly reduced CCL2 levels, suppressed monocyte/macrophage infiltration, repaired BBB/BOB integrity, and reversed anxiety-like behaviors.

Conclusions:

• The engineered nanocomplex offers a potent dual-action strategy by blocking inflammation and restoring barrier integrity in the eye-brain axis.
• This approach represents a novel paradigm for treating HM-related anxiety and other inter-organ crosstalk disorders.
• TK-F-PEI/siR@A shows promise as a targeted therapy for conditions involving inflammation and barrier dysfunction.