Bioinspired Proteome‐Engineered Hydrogels as Vitreous Substitutes for Preserving Intraocular Homeostasis

Current vitreous substitutes, failing to recapitulate the dynamic proteomic microenvironment essential for retinal homeostasis, often cause complications like increased intraocular pressure, proliferative vitreoretinopathy and macular edema. Herein, we propose a proteome-directed vitreous microenvironment engineering strategy, pioneering a paradigm that goes beyond structural replacement by actively restoring the proteomic homeostasis intrinsic to the native vitreous. Specifically, a photo-crosslinked network is engineered by integrating hyaluronic acid methacrylate and polyethylene glycol methacrylate, achieving exceptional (>90%) retention of endogenous vitreous proteins (e.g., COL2A1, COL3A1, FBLN1, FBLN2). This engineered vitreous-mimetic properties, featuring high optical transmittance, a physiological refractive index and tailored viscoelasticity. Crucially, small-angle X-ray scattering reveals a dual-mesh architecture (ξ = 13-47.5 nm) of the network, facilitating selective diffusion of small molecules while immobilizing homeostatic proteins. In a rabbit vitrectomy model, this network exhibits long-term structural stability in supporting retina, demonstrates good biocompatibility, and preserves the endogenous vitreous proteome without causing observable adverse effects. This work introduces a promising platform for intraocular biomaterial design by integrating proteomic functionality to dynamically form a homeostatic microenvironment, offering a safe intraocular tamponade for vitreoretinal pathologies.