ROS-pH Dual-Responsive Polydopamine Nanoparticles for Targeted Fasudil Delivery Ameliorate Multiple Pathologies in Diabetic Retinopathy

Jiaqi Li,1,* Zheng Zhong,1,* Yuhe Tan,1 Xiaohong Ma,1 Ruohong Wang,1 Guoyao Gao,2 Xian Zhang,1 Ziqing Zhou,1 Yin Zhao,1,* Jia Liu,3 Xufang Sun4 1Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Otolaryngologic and Ophthalmic Diseases, Wuhan, 430068, People’s Republic of China; 2Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 3Key Laboratory of Fermentation Engineering (Ministry of Education), National “ 111” Center for Cellular Regulation and Molecular Pharmaceutics, School of Life and Health Sciences, Hubei University of Technology, Wuhan, 430068, People’s Republic of China; 4Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Otolaryngologic and Ophthalmic Diseases, Key Laboratory of Vascular Aging (Ministry of Education), Wuhan, 430068, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xufang Sun; Jia Liu, Email sunxufang2016@163.com; jialiu1207@126.comBackground: The multifaceted pathogenesis of diabetic retinopathy (DR) involves numerous pathways, among which oxidative stress and Rho-associated kinase (ROCK) signaling are critically implicated. The failure of current anti-VEGF monotherapies to address these key pathological processes limits their efficacy. While the ROCK inhibitor Fasudil is a promising candidate, its clinical translation for DR is hindered by poor ocular retention and lack of target specificity.Methods: We engineered a reactive oxygen species (ROS)- and pH-dual responsive polydopamine nanoplatform (Fasudil@PDA) to deliver Fasudil while concurrently scavenging oxidative stressors.Results: The Fasudil@PDA nanoparticles achieved a high drug loading capacity of ~28%. The release kinetics were specifically engineered to be responsive to the DR microenvironment. Under high ROS conditions in vitro, the platform demonstrated a sustained and efficient release profile, achieving a cumulative release of 87.3% over 56 days — demonstrating remarkable longevity. Separately, the pH-responsive drug release capability was also confirmed under acidic conditions. The platform effectively neutralized multiple ROS species in vitro and significantly restored endothelial barrier integrity by inhibiting the ROCK/MLC pathway. In a laser-induced choroidal neovascularization model, a single injection suppressed pathological angiogenesis by 45%. In diabetic mice, the same treatment markedly reduced vascular leakage, attenuated neuroinflammation, and restored retinal function, with b-wave amplitudes recovering to near-normal levels.Conclusion: This study establishes a multi-faceted nanotherapeutic strategy that synergizes sustained, long-acting ROCK inhibition with innate antioxidant activity. Designed to be activated by the pathological cues of DR, including acidic pH and ROS, our approach precisely targets multiple pathological pathways, offering a promising and translatable paradigm for overcoming the limitations of current monotherapies.