A sequentially targeted and pathology-responsive nanoplatform for synergistic treatment of dry eye disease via concurrent anti-inflammation and mitochondrial ROS scavenging.

The treatment of complex inflammatory diseases like dry eye disease (DED) is hampered by the intertwined pathologies of inflammation and oxidative stress, which form a self-amplifying vicious cycle. Here, we report an intelligent nanoplatform (CFMPDA) designed to actively navigate and disrupt this cycle through sequential, pathology-responsive targeting. CFMPDA is constructed by encapsulating the anti-inflammatory agent Fuziline within a mesoporous polydopamine (MPDA) nanoscavenger and conjugating CCL2-targeting antibodies on its surface. This design enables a two-stage therapeutic strategy: first, CCL2-mediated anchoring to the inflamed cornea, providing disease severity-dependent retention that overcomes rapid ocular clearance; second, subsequent mitochondrial targeting to deliver combined anti-inflammatory and antioxidant therapy directly to the organelle generating pathogenic ROS. In vivo, CFMPDA demonstrated potent, synergistic efficacy in a DED mouse model, simultaneously suppressing the inflammatory cascade (IL-1β, IL-6, TNF-α, MMP9, T cell infiltration) and quenching oxidative stress, leading to comprehensive tissue repair and functional recovery that surpassed the clinical standard-Fluorometholone. This work establishes a versatile nanotechnology blueprint-responsive bio-interfacing coupled with programmed subcellular delivery-for the synergistic treatment of inflammatory disorders characterized by chemokine upregulation and mitochondrial dysfunction.