Platelet Membrane‐Camouflaged ROS‐Responsive Nanoplatform for Targeted Delivery and Sustained Release of Verteporfin to Modulate Hippo Signaling Pathway in Glaucoma Therapy

Abstract Glaucoma, a major contributor to permanent vision loss globally, primarily involves abnormal extracellular matrix (ECM) deposition in the trabecular meshwork (TM), resulting in elevated aqueous humor outflow resistance. Elevated intraocular pressure (IOP) causes nuclear translocation of Yes‐associated protein (YAP) and transcriptional co‐activator with PDZ‐binding motif (TAZ). This process inhibits Hippo signaling, accelerating pathological advancement. While the YAP inhibitor verteporfin (VP) effectively blocks YAP/TAZ nuclear translocation during ECM remodeling and demonstrates the potential for IOP normalization, its clinical translation for glaucoma therapy remains limited by poor target specificity and rapid clearance. To address these challenges, a biomimetic drug delivery system (PM@SPE/VP), enabling targeted TM accumulation and sustained VP release is developed. PM@SPE/VP introduces hyperbranched polyphosphoester (SPE) containing thioether bonds as a matrix to achieve ROS‐responsive VP release and prolonged therapeutic time. Furthermore, inspired by the intense interaction between the platelet membrane (PM) and exposed collagen in the TM, the nanoparticle is camouflaged by PM to precisely anchor in the TM tissue. In the steroid‐induced ocular hypertension (OHT) mouse model, intracamerally administered PM@SPE/VP achieved a 47.7% IOP reduction sustained for 14 days. Together, this exquisitely designed nanoplatform represents a promising intracameral VP formulation, offering new possibilities for effective and sustained glaucoma management.