Dry eye disease (DED) is a chronic ocular surface disorder characterized by tear-film hyperosmolarity and sustained inflammation. Conventional therapies based on small molecules or antibodies frequently show limited efficacy because they typically act on single targets, are associated with adverse side effects, and exhibit poor ocular bioavailability. In contrast, oligonucleotide therapeutics, including small interfering RNA (siRNA), antisense oligonucleotides (ASOs), microRNA (miRNA) modulators, and aptamers, enable precise, gene-level modulation of pathogenic pathways, while offering multi-target capacity, high specificity, and favorable safety profiles. These attributes position oligonucleotide therapeutics as promising candidates for interrupting the self-perpetuating cycle of inflammation and hyperosmolarity that underlies DED pathogenesis. This review summarizes the molecular mechanisms of oligonucleotide-based drugs, their current status in clinical translation, and recent advances in delivery strategies and degradation control for ocular applications. Persistent challenges, including nuclease susceptibility, limited tissue penetration, inefficient endosomal escape, and the difficulty of achieving sustained delivery are discussed, while outlining future directions, with particular emphasis on integration with targeted protein degradation strategies and the development of next-generation delivery platforms optimized for ocular surface administration. By balancing opportunities with existing limitations, this review aims to support mechanistic understanding and guide the rational development of oligonucleotide-based therapies for DED. • Oligonucleotide therapeutics enable precise gene-level intervention for dry eye disease. • SiRNA, miRNA, and aptamers target inflammatory pathways with high specificity. • Clinical translation faces challenges in stability, delivery, and patient heterogeneity. • Integration with protein degradation strategies enhances DED therapeutic potential. • Advanced delivery systems improve ocular bioavailability and treatment durability.
Yin et al. (2026) studied this question.