ROS-responsive transmembrane peptide-antibody conjugate eyedrops for the non-invasive treatment of choroidoretinopathy.

Choroidoretinopathy is a major public health concern that causes significant vision impairment. Although therapeutic antibodies have demonstrated potential in treating these conditions, intravitreal injections remain invasive, associated with adverse effects, and require repeated traumatic administrations. Non-invasive drug delivery methods, such as eye drops, represent an ideal alternative but are limited by ocular barriers, making it difficult for drugs to effectively reach specific lesions. In this study, we introduce a novel reactive oxygen species (ROS)-responsive transmembrane peptide-antibody conjugate (PAC) designed for non-invasive, precise antibody delivery to the deep fundus region. The responsive PAC, termed trans-activator of transcription-polyethylene glycol-maleimide (TAT-MPEG)-antibody, is synthesized by linking transmembrane peptides TAT to maleimide via ROS-sensitive diselenide bonds, enabling efficient antibody conjugation. Following eye drop administration, TAT enhances ocular penetration, allowing the conjugate to traverse ocular barriers and deliver antibodies directly to the posterior segment. Moreover, the diselenide bonds facilitate antibody release in oxidative environments, ensuring targeted drug localization at disease sites. In mouse models of choroidal neovascularization and choroidal melanoma, this conjugate demonstrated significant therapeutic efficacy, highlighting its broad clinical potential for the treatment of choroidoretinopathy.