A Noninvasive Nanoeyedrop Therapy for the Inhibition of Uveal Melanoma: Tetrahedral Framework Nucleic Acid–Based Bioswitchable MicroRNA Delivery System

Uveal melanoma (UM) is the most prevalent primary intraocular malignancy, exhibiting pronounced invasive characteristics and a dismal prognosis. Conventional therapeutic modalities, including radiotherapy, laser therapy, and surgery, are frequently invasive and can lead to complications, underscoring the need for the development of efficacious, safe, and noninvasive therapeutic approaches. This study investigated a tetrahedral framework nucleic acid (tFNA)-based bioswitchable microRNA (miRNA) delivery system, designated BiRDS, engineered for the inhibition of UM through the use of miRNA suppressors via noninvasive eyedrops. The BiRDS construct exhibited a tetrahedral structure, which was small in size, easily synthesizable, stable, and biosafe, and was able to efficiently carry miR-30a-5p into UM cells. Functionally, BiRDS was observed to inhibit the proliferation, migration, and invasion of UM cells while promoting apoptosis through the miR-30a-5p/E2F7 axis. It is noteworthy that BiRDS nanoeyedrops were able to penetrate the complex ocular barrier structure and reach the fundus, thereby inhibiting the growth of UM in a xenograft model. As a patient-friendly, eyedrop-based miRNA delivery system, BiRDS not only inhibited UM without enucleation of the eyeball but was also expected to improve patient compliance and quality of life while providing a safer alternative for ocular drug administration. This work substantiates BiRDS nanoeyedrops as a potential paradigm shift in the local treatment of early UM, facilitating its application in treating other ocular diseases via miRNA therapies.