Small Nucleic Acid Therapeutics for Ocular Diseases: Progress, Challenges, and Future Perspectives.

Abstract

Ocular diseases remain a major global health challenge with substantial unmet therapeutic needs. Small nucleic acid therapeutics offer a precise strategy to regulate disease-related mRNAs or noncoding RNAs through base pairing, thereby modulating protein expression at the RNA level. Major modalities include antisense oligonucleotides, small interfering RNAs, microRNA-based therapeutics, small activating RNAs, and nucleic acid aptamers, which act through RNA degradation, RNA interference, splicing modulation, microRNA regulation, transcriptional activation, or structure-dependent target binding. These properties make them attractive for ocular diseases involving genetic defects, pathological angiogenesis, inflammation, fibrosis, or neurodegeneration. However, their clinical translation in ophthalmology remains limited by poor molecular stability, insufficient tissue retention, immune activation, off-target effects, and inefficient delivery to target ocular tissues. Rational oligonucleotide design, appropriate local administration routes, and optimized delivery platforms are therefore essential for improving stability, tissue penetration, cellular uptake, and therapeutic durability. This review summarizes the major classes, mechanisms, chemical modification strategies, ocular delivery systems, and therapeutic applications of small nucleic acid drugs in ophthalmology. We also discuss lessons from clinical successes and failures and propose future directions for safe, durable, and individualized ocular therapy.