**Background:** The global therapeutic protein market has grown significantly, from 90.53 billion USD in 2020 to 98.1 billion USD in 2021, and is projected to reach 155.06 billion USD by 2025. Ocular diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD), glaucoma, and posterior uveitis are major causes of visual impairment, affecting 596 million people in 2020, with projections of 895 million by 2050. Therapeutic proteins and peptides offer advantages over small molecules, including lower toxicity, high potency, and minimal drug-drug interactions, but face challenges like short half-lives, instability, poor permeability, and immunogenicity. This review provides a comprehensive overview of proteins and peptides used in ocular disorders, delivery challenges, and novel strategies to enhance ocular bioavailability.
**Methods:** This is a narrative review that synthesizes information from published literature on protein and peptide drugs for ocular diseases. It covers anti-VEGF agents (e.g., ranibizumab, aflibercept, brolucizumab, faricimab), anti-TNF-α agents (e.g., adalimumab, infliximab), GLP-1 agonists (e.g., liraglutide, semaglutide), tissue plasminogen activator (TPA), and neurotrophic growth factors (NGF). The review discusses physicochemical barriers (hydrophilicity, high molecular weight, metabolic instability), static and dynamic ocular barriers (cornea, conjunctiva, sclera, blood-aqueous barrier, blood-retinal barrier), enzymatic barriers, and formulation issues. Strategies to enhance bioavailability include selecting optimal routes (topical, periocular, intraocular such as intravitreal, intrastromal, intracameral, suprachoroidal), chemical modifications (PEGylation, Fc-fusion), and novel delivery systems (polymeric nanoparticles, lipid nanoparticles, hydrogels, dendrimers, cell-penetrating peptides, microneedles, iontophoresis, port delivery systems, nanowafers, microbubbles, and combination systems).
**Key Results:** The review reports specific data from clinical trials and preclinical studies. For example, ranibizumab improved vision in 40% of patients and prevented vision loss in approximately 95% of patients. Faricimab in phase 3 trials (TENEHAYA and LUCERNE) showed a mean BCVA letter difference of 0.7 letters (5.8 vs 5.1 letters) and 0 letters (6.6 vs 6.6 letters) compared to aflibercept. In DME trials (RHINE and YOSEMITE), faricimab showed a difference of 1.5 ETDRS letters (11.8 vs 10.3) and -0.2 ETDRS letters (10.7 vs 10.9). Abicipar pegol in phase 3 trials (SEQUOIA and CEDAR) showed stable vision in 93.2%, 91.3%, and 95.8% of patients in different groups, but intraocular inflammation (IOI) occurred in 16.8%, 20.4%, and 4% of groups, leading to FDA non-approval. Bevacizumab-loaded PLGA nanoparticles (197 nm, 82.4% encapsulation) prolonged vitreous residency, with maximum concentration at 7 days. Bevacizumab-loaded multivesicular liposomes showed 80% encapsulation efficiency, slower clearance, and twice the area under the curve compared to solution. Hydrogels (e.g., hyaluronic acid/dextran) maintained therapeutic concentrations for at least 6 months in rabbits. Microneedle delivery of bevacizumab reduced corneal neovascularization by 44% in rabbits. Iontophoresis delivered 0.6 mg of bevacizumab in 20 min in rabbits, delaying retinal neovascularization by 4 weeks.
**Clinical Implications:** The review emphasizes that while many novel delivery systems show promise in enhancing ocular bioavailability, sustained release, and patient compliance, no single system addresses all challenges. Intravitreal injections remain the most effective route but are invasive and associated with adverse effects. Strategies like PEGylation (e.g., pegaptanib) and Fc-fusion (e.g., aflibercept) have improved half-life and efficacy. Nanocarriers (PLGA, chitosan, liposomes) and hydrogels offer controlled release and reduced dosing frequency. However, toxicity, immunogenicity, and regulatory hurdles remain. The review calls for more research on combination systems, long-term safety, and clinical translation to improve treatment of ocular diseases and reduce the global burden of visual impairment.