Ocular gene therapy holds transformative potential for the treatment of both hereditary and acquired eye diseases by addressing their underlying genetic causes rather than merely alleviating symptoms. This review synthesizes two interdependent pillars that are critical to therapeutic success. First, advances in molecular tool engineering have enabled a diverse and increasingly precise spectrum of genomic interventions. Platforms derived from clustered regularly interspaced short palindromic repeats, along with antisense oligonucleotides and small interfering RNA, support strategies ranging from allele-specific silencing to functional gene augmentation and in situ correction. Collectively, these technologies expand the repertoire of druggable targets and enable mutation-specific therapeutic design across a broad range of ocular disorders. Second, innovations in delivery platforms are essential for overcoming the unique anatomical and physiological barriers of the eye. Progress in this area includes the development of engineered adeno-associated virus (AAV) capsids with enhanced cellular tropism, as well as lipid nanoparticles (LNPs) with tunable physicochemical properties achieved through lipid composition and surface ligand modification. To address limitations in payload capacity, dual-AAV vector systems have been developed for large transgenes, while virus-like particles and LNPs enable transient delivery of diverse cargo types, including RNA, proteins, and ribonucleoprotein complexes. These advances significantly broaden both delivery modalities and therapeutic flexibility. Notably, LNP-based systems also support repeat dosing, offering an advantage over viral vectors. Beyond summarizing preclinical advances, this review examines the current landscape of clinical translation, including the landmark approval of Luxturna® for RPE65-associated retinal dystrophy and ongoing early-phase trials targeting a spectrum of diseases. These include inherited retinal disorders such as retinitis pigmentosa and Leber congenital amaurosis, as well as complex acquired conditions including glaucoma, age-related macular degeneration, and herpetic keratitis. Finally, we discuss persistent challenges, including immunogenicity, delivery efficiency, and mutational heterogeneity, and outline future directions toward next-generation precision therapies in ophthalmology. • CRISPR-derived platforms alongside ASOs and siRNA enable precise gene editing for ocular diseases • Engineered AAV capsids enhance targeted ocular delivery, while LNPs and VLPs expand therapeutic payload options • Clinical advances target inherited and acquired eye disorders
孔令芸 et al. (2026) studied this question.