Stereospecific Peptide–Polysaccharide Conjugates Enable Noninvasive Therapy of Neovascular Age-Related Macular Degeneration

Abstract

Therapeutic interventions for posterior segment ocular diseases, including neovascular age-related macular degeneration (nAMD), remain constrained by poor intraocular bioavailability and the need for repeated intravitreal injections. Here, we introduce a noninvasive therapeutic strategy based on stereospecific peptide–polysaccharide conjugates (PPC) for efficient nAMD treatment. A controllable synthetic strategy was established to generate stereospecific L-PPC and D-PPC, among which D-PPC displayed pronounced chirality-dependent bioactivity, characterized by high-affinity binding to integrin receptors and enhanced inhibition of endothelial/epithelial cell proliferation and migration. Following topical administration, D-PPC efficiently overcame ocular barriers and penetrated choroidal lesions while markedly suppressing pathological angiogenesis in a laser-induced choroidal neovascularization mouse model, comparable to that of intravitreal ranibizumab. We elucidated that stereospecific D-PPC modulates key molecular programs in vivo, including T-cell receptor signaling and cell adhesion molecule pathways. Notably, D-PPC exhibited no detectable ocular or systemic toxicity. This study establishes chirality-engineered peptide–polysaccharide conjugates as a noninvasive and effective therapeutic for posterior ocular diseases, providing a structural and mechanistic blueprint for future translational ophthalmic applications.