Current pharmacotherapy for DED is limited by a vicious inflammatory cycle in which reactive oxygen species (ROS) play a critical role. Additionally, topical eye drop therapy for DED often suffers from poor ocular availability due to multiple ocular surface barriers. Considering the key role of the ROS-NLRP3-IL-1β signaling axis in DED, in this investigation, fluorinated multifunctional polymer vesicles were developed for enhanced ocular surface penetration and synergistic DED therapy by combining ROS scavenging and immunomodulation. MCC950, an NLRP3-IL-1β inhibitor, was loaded in situ during vesicle preparation. The results demonstrated that fluorocarbon units randomly distributed in the corona layer significantly enhanced ocular surface penetration. Furthermore, the vesicle membrane, composed of polyphenylborate ester blocks, efficiently scavenged excess ROS in inflamed corneal tissue. In response to excessive ROS, a hydrophobic-to-hydrophilic conversion of the vesicle membrane facilitated the efficient release of MCC950 to modulate the NLRP3-caspase-1-IL1β pathway. We believe that this work will provide insightful guidance to achieve effective treatment of DED by enhancing ocular surface penetration.