Dendrimer-mediated co-delivery of curcumin and miR-146a attenuates dry eye disease

Dry eye disease (DED) is a highly prevalent ocular disorder affecting an estimated 5-50% of the global population. Despite its substantial clinical burden, effective therapeutic options remain limited owing to the multifactorial nature and complex pathophysiology of the disease. To simultaneously address the two principal pathological drivers of DED, oxidative stress and chronic inflammation, we engineered mRC@PAM, a polyamidoamine (PAMAM) dendrimer-based nanotherapeutic eye-drop system capable of co-delivering curcumin (Cur) and microRNA-146a (miR-146a) through hydrophobic encapsulation and electrostatic complexation, respectively. The resulting nanoformulation exhibited excellent physicochemical stability, high cargo-loading efficiency, outstanding biocompatibility, and prolonged retention on the ocular surface. Mechanistically, mRC@PAM effectively restored intracellular redox balance by preserving antioxidant defense capacity and maintaining mitochondrial membrane integrity. Simultaneously, it attenuated inflammatory responses through miR-146a-mediated suppression of interleukin-1 receptor-associated kinase 1 (IRAK1), leading to inhibition of the nuclear factor kappa B (NF-κB) signaling cascade and subsequent regulation of macrophage polarization. In vivo, treatment with mRC@PAM markedly reduced reactive oxygen species (ROS) accumulation and apoptotic cell death in corneal tissues, promoted recovery of the corneal epithelium and conjunctival goblet cells, diminished inflammatory cell infiltration, and significantly enhanced tear-film stability. Taken together, these findings highlighted mRC@PAM as a promising dual-action nanotherapeutic platform capable of concurrently mitigating oxidative and inflammatory damage, thereby offering a potential treatment strategy for DED and other ocular surface disorders characterized by intertwined oxidative stress and inflammatory pathologies.