Therapeutic proteins, including monoclonal antibodies, single chain variable fragment (ScFv), crystallizable fragment (Fc), and fragment antigen binding (Fab), have accounted for one-third of all drugs on the world market. In particular, these medicines have been widely used in ocular therapies in the treatment of various diseases, such as age-related macular degeneration, corneal neovascularization, diabetic retinopathy, and retinal vein occlusion. However, the formulation of these biomacromolecules is challenging due to their high molecular weight, complex structure, instability, short half-life, enzymatic degradation, and immunogenicity, which leads to the failure of therapies. Various efforts have been made to overcome the ocular barriers, providing effective delivery of therapeutic proteins, such as altering the protein structure or including it in new delivery systems. These strategies are not only cost-effective and beneficial to patients but have also been shown to allow for fewer drug side effects. In this review, we discuss several factors that affect the design of formulations and the delivery of therapeutic proteins to ocular tissues, such as the use of injectable micro/nanocarriers, hydrogels, implants, iontophoresis, cell-based therapy, and combination techniques. In addition, other approaches are briefly discussed, related to the structural modification of these proteins, improving their bioavailability in the posterior segments of the eye without affecting their stability. Future research should be conducted toward the development of more effective, stable, noninvasive, and cost-effective formulations for the ocular delivery of therapeutic proteins. In addition, more insights into preclinical to clinical translation are needed.
Keywords: barriers of corneal tissues; cell-penetrating peptides; hydrogels; microcarriers; nanocarriers; ocular diseases; sustained ocular delivery; therapeutic proteins.