This study developed BiRDS, a bioswitchable miR-22 nanocarrier deliverable via non-invasive ocular surface routes, which effectively suppresses pathological neovascularization while protecting retinal neuronal function, overcoming the limitations of traditional intravitreal injections.
Literature Overview
The article titled 'Extraocular delivery of bioswitchable tri-miR-22-loaded tetrahedral DNA nanostructures for intraocular neovascular and neurodegenerative repair,' published in Signal Transduction and Targeted Therapy, reviews and summarizes the design, synthesis, and therapeutic potential of BiRDS—a tetrahedral DNA framework-based delivery system for miR-22 mimics—in treating retinal neovascularization and neurodegenerative diseases. The study demonstrates that BiRDS achieves effective penetration into the choroid and retina via subconjunctival injection, significantly inhibiting pathological angiogenesis and improving retinal perfusion and neuronal integrity without requiring intravitreal administration. By modulating the Wnt/β-catenin signaling pathway, this system exerts dual therapeutic effects, offering a novel, non-invasive strategy for treating diabetic retinopathy, age-related macular degeneration, and similar conditions. The research further validates its high efficacy and safety in mouse models, highlighting its broad clinical potential as a next-generation RNA nanotherapeutic.Background Knowledge
Retinal neovascular and neurodegenerative diseases—such as diabetic retinopathy (DR), wet age-related macular degeneration (wAMD), and retinopathy of prematurity (ROP)—are leading causes of irreversible vision loss. These conditions share common features including abnormal blood vessel proliferation, vascular leakage, and progressive retinal neuronal damage. Current first-line therapies targeting vascular endothelial growth factor (VEGF) can control leakage, but 30–50% of patients fail to respond. Moreover, long-term, frequent intravitreal injections carry risks such as endophthalmitis and retinal detachment, reducing patient compliance. Additionally, anti-VEGF therapies primarily address vascular abnormalities without providing neuroprotection, failing to restore vascular architecture or alleviate ischemia. Therefore, there is an urgent need for novel treatments that simultaneously inhibit pathological angiogenesis and protect neurons. MicroRNA (miR-22) has been shown to possess dual anti-angiogenic and neuroprotective functions, but its clinical application is limited by poor stability, rapid degradation, and low cellular uptake efficiency. Tetrahedral framework nucleic acids (tFNAs) are ideal nucleic acid delivery vehicles due to their excellent biocompatibility, high tissue permeability, and ability to efficiently enter cells without transfection reagents. This study leverages this platform to construct BiRDS, an enzyme-activatable nanosystem carrying three copies of miR-22, aiming to achieve efficient delivery via extraocular routes, overcoming limitations of conventional administration methods and offering a safer, minimally invasive, and comprehensive solution for retinal disease therapy.
Research Methods and Experiments
Researchers designed and synthesized a tetrahedral DNA nanostructure, BiRDS, carrying three miR-22 mimics, leveraging its unique spatial conformation for efficient cellular uptake and RNase H-responsive release. Structural integrity and particle size distribution were confirmed using native gel electrophoresis, transmission electron microscopy, atomic force microscopy, and dynamic light scattering. In vitro studies used hypoxia-exposed human umbilical vein endothelial cells (HUVECs) to evaluate BiRDS’s effects on cell proliferation, migration, and tube formation. In vivo studies employed laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) mouse models. Fluorescein fundus angiography (FFA), optical coherence tomography (OCT), and retinal flat-mount staining were used to analyze vascular leakage and neovascular area. Cy5 labeling tracked BiRDS distribution in ocular tissues, verifying its penetration following subconjunctival injection. Immunofluorescence staining assessed retinal neuron survival, while electroretinography (ERG) evaluated visual function. Transcriptome sequencing, combined with qPCR, Western blot, and immunofluorescence, validated the regulatory role of the Wnt/β-catenin signaling pathway.Key Conclusions and Perspectives
Research Significance and Prospects
The BiRDS system presented in this study represents an innovative RNA nanotherapy that overcomes the invasive limitations of traditional intravitreal injections by enabling efficient intraocular delivery via extraocular routes. Its dual therapeutic functionality—simultaneously inhibiting pathological neovascularization and protecting neurons—addresses the shortcomings of current anti-VEGF therapies, offering a more comprehensive treatment strategy for retinal diseases. The modular design of BiRDS allows for future loading of other therapeutic nucleic acids, expanding its potential applications in gene therapy.
Although it demonstrates excellent efficacy in mouse models, its delivery efficiency in larger eyes (e.g., non-human primates), long-term safety, and tolerability upon repeated dosing require further validation. Additionally, more systematic biodistribution, pharmacokinetic, and toxicological studies are needed to support clinical translation. Future research could explore its application in other retinal vascular diseases such as diabetic retinopathy and retinal vein occlusion, and investigate synergistic effects when combined with other therapeutic approaches.
Conclusion
This study successfully developed and validated BiRDS, a tetrahedral DNA nanostructure-based miR-22 delivery system that enables efficient intraocular penetration via subconjunctival injection, significantly suppressing pathological neovascularization and preserving retinal neuronal function. Compared to existing anti-VEGF therapies, BiRDS not only effectively controls vascular leakage but also promotes healthy vascular remodeling, improves retinal perfusion, and maintains neuronal structure and electrophysiological function, demonstrating broader therapeutic advantages. Mechanistic studies indicate that its efficacy is primarily achieved through inhibition of the Wnt/β-catenin signaling pathway. This platform overcomes the challenges of poor stability and low delivery efficiency associated with conventional RNA therapies, while avoiding complications from repeated intravitreal injections. It offers a minimally invasive, long-acting, and multifunctional therapeutic strategy for retinal diseases such as diabetic retinopathy and wet macular degeneration. Future studies should validate its long-term safety and efficacy in larger animal models to advance clinical translation, positioning BiRDS as a promising next-generation RNA nanotherapeutic tool for retinal diseases.
