Diabetes mellitus is a highly prevalent, chronic systemic metabolic disorder affecting populations worldwide. According to the most recent data from the International Diabetes Federation (IDF), the global prevalence of diabetes among adults stands at 10.5%, whereas in China, it reaches 11.6%-corresponding to approximately 113.9 million affected adults, the highest absolute number globally. Diabetes-related systemic and ocular complications significantly impair patients' quality of life and impose substantial economic burdens on individuals, families, and healthcare systems, thereby constituting a pressing public health challenge requiring coordinated national and international action. Diabetic ocular surface disease (DOSD) represents one of the earliest and most frequently observed ocular complications of diabetes, often preceding other diabetic eye manifestations. Its incidence rises markedly with longer disease duration and suboptimal glycemic control. Notably, diabetic patients undergoing common ophthalmic procedures-including phacoemulsification for cataract, pterygium excision, and vitreoretinal surgery-are at heightened risk of postoperative keratoconjunctival disorders, which may progress to irreversible visual impairment or blindness, thereby threatening long-term ocular integrity. Among individuals with diabetes of ≥5 years' duration, over 60% develop moderate-to-severe dry eye or keratoconjunctival epithelial damage, clinically characterized by progressive symptoms including ocular dryness, foreign body sensation, photophobia, pain, and, in advanced cases, vision loss-collectively resulting in marked functional and quality-of-life deterioration.
Current clinical management of DOSD remains largely palliative, relying predominantly on artificial tear supplementation, secretagogues, and topical anti-inflammatory agents. However, these interventions do not address underlying neuroepithelial dysfunction and are limited by poor long-term adherence-reported rates fall below 50%-leading to suboptimal therapeutic outcomes. Consequently, the development of mechanism-targeted, disease-modifying therapies for DOSD is an urgent unmet clinical need.
Antisense oligonucleotides (ASOs) are synthetic, single-stranded RNA molecules designed to bind complementary tRNA-derived fragments (tRFs) with high specificity, thereby inhibiting their pathogenic activity. ASO-based therapeutics have demonstrated robust efficacy in neurodegenerative disorders, with several candidates having advanced to late-stage clinical trials. Engineered exosomes represent a next-generation drug delivery platform, offering enhanced nucleic acid loading capacity, improved pharmacokinetic stability, increased bioavailability, and superior tissue targeting compared with conventional exosomes or free small-molecule drugs. In ophthalmology, scalable production of engineered exosomes has opened new avenues for localized treatment of keratoconjunctival diseases. Furthermore, hydrogels provide physical encapsulation of nucleic acid therapeutics, shielding them from rapid enzymatic degradation in vivo; when combined with the intrinsic lipid bilayer of exosomes, this creates a synergistic "dual-barrier" protection system that markedly enhances therapeutic durability and clinical translatability. Poly(β-amino ester) (PAE) hydrogels-fabricated as biocompatible, three-dimensional scaffolds-retain the favorable properties of conventional hydrogels while additionally enabling sustained, controlled release, scalable manufacturing, and intrinsic neuroregenerative potential. In preclinical studies using a murine model of diabetic ocular surface disease, topical application of PAE hydrogel loaded with tRF-targeting ASO-engineered mesenchymal stem cell-derived exosomes (tRF-ASO-Exo) significantly attenuated ocular surface inflammation, promoted structural recovery of the corneal and conjunctival epithelium, and preserved corneal epithelial viability.
This study aims to evaluate a novel, non-invasive, topical hydrogel-based delivery system for tRF-ASO-loaded mesenchymal stem cell-derived exosomes (MSC-Exos) in patients with DOSD. The primary objective is to assess structural and functional ocular surface restoration using multimodal imaging and clinical metrics: anterior segment optical coherence tomography (AS-OCT), in vivo confocal microscopy (IVCM), slit-lamp-guided corneal fluorescein staining, and quantitative corneal sensitivity testing. Symptom improvement will be evaluated using the validated Ocular Surface Disease Index (OSDI). Secondary endpoints include tear secretion volume (Schirmer test), tear film breakup time (TBUT), ocular redness grading, tear meniscus height (via AS-OCT), and best-corrected visual acuity (BCVA).
A total of 30 participants will be enrolled and randomized into three intervention groups. Following a 14-day placebo run-in period-during which all subjects receive bilateral placebo eye drops (one drop per eye, twice daily, approximately 12 hours apart)-participants will receive active treatment for 84 days: Group 1 (Exo) receives 10 μg/drop of unmodified MSC-Exos; Group 2 (tRF-ASO-Exo) receives 10 μg/drop of MSC-Exos formulated in PAE hydrogel; and Group 3 (tRF-ASO-Exo-PAE) receives 10 μg/drop of tRF-ASO-engineered MSC-Exos delivered via PAE hydrogel-all administered twice daily. A 12-weeks follow-up will be conducted to monitor disease progression and durability of therapeutic effects.
