Buoyancy-Mediated in Situ Phase-Transition Microbubbles Enable Efficient Aqueous Humor Drug Delivery for Accelerated Corneal Endothelial Regeneration

Abstract The corneal endothelium plays a pivotal role in maintaining corneal clarity, and its damage leads to a hydration dysfunction and secondary glaucoma. We previously identified XMU-MP-1, a Hippo pathway inhibitor, as a potent stimulator of corneal endothelial cell proliferation in nonhuman primate models. However, its therapeutic potential is limited by poor intraocular permeability and low bioavailability. Herein, we report an engineered perfluoropentane (PFP)-cored lipid microbubble (MB) platform for the buoyancy-mediated targeted delivery of XMU-MP-1. Post intracameral injection, drug-loaded microbubbles (D@MB) undergo spontaneous in situ liquid-to-gas phase transition at physiological temperature, which grants them buoyancy-driven upward movement in aqueous humor to maintain continuous direct contact with the endothelial layer, achieving an extended retention of over 72 h in the anterior chamber. Finally, the D@MB drug delivery platform accelerates regenerative processes and restores both the corneal ultrastructure and physiological function. This study highlights a minimally invasive approach that bypasses traditional surgical interventions to stimulate the repair of the damaged corneal endothelium.