Dual-Dynamically Crosslinked Nanogels Enable Prolonged Ocular Retention for Multimodal Dry Eye Therapy

Dry eye disease (DED), a chronic disorder affecting nearly half the global population, is perpetuated by oxidative stress, inflammation, and tear film instability. Constrained by short precorneal residence and monotherapy, DED therapies necessitate frequent dosing and polypharmacy, leaving unmet needs for prolonged ocular retention and multimodal intervention. Herein, we develop berberine (BBR)-loaded dual-dynamically crosslinked nanogels (BBR@MPN-NGs) integrating tannic acid (TA)-zinc metal-polyphenol networks with carboxymethyl chitosan/aldehyde-functionalized poly(ethylene glycol) Schiff base networks, enabling a single-platform multimodal therapy combining antioxidant, anti-inflammatory, and lubricating capacities. Capitalizing on dual-dynamic synergy, BBR@MPN-NGs exhibit 1-year colloidal and antioxidant stability alongside lubricity, while leveraging TA-mediated adhesion and Schiff base reversibility to sustain corneal BBR exposure for 24 h, enabling once-daily dosing. In murine DED models, BBR@MPN-NGs outperform first-line cyclosporine A and dexamethasone in promoting corneal epithelial repair and tear secretion. Mechanistically, the nanogels reprogram the pathological microenvironment by scavenging reactive oxygen species, attenuating pro‑inflammatory macrophage polarization, and suppressing c-Jun N-terminal kinase signaling to reduce pro-inflammatory gene expression. Notably, the preservative-free nanogels passed sterility and endotoxin testing, showing no ocular or systemic toxicity, which supports biosafety. These dual-dynamically crosslinked nanogels enable reduced-frequency and shortened treatment duration, offering an integrated strategy for complex ocular surface diseases requiring sustained multimodal intervention.