Nanocarrier-based CircRNA therapeutics in inherited retinal dystrophies

Abstract

Inherited retinal dystrophies (IRDs) are a genetically diverse group of progressive blinding disorders with limited curative options. Despite advances in gene therapy, most IRD subtypes remain untreatable due to genetic heterogeneity and delivery challenges. Circular RNAs (circRNAs), a class of stable non-coding RNAs, have emerged as novel modulators of retinal gene expression. Recent developments in nanocarrier technology enable targeted delivery of circRNA mimics and inhibitors to retinal tissues, offering a promising therapeutic alternative. These platforms utilize lipid nanoparticles, polymeric micelles, and exosomes to bypass the blood-retinal barrier and enhance cellular uptake. Preclinical studies demonstrate restoration of photoreceptor survival pathways and delayed retinal degeneration in murine IRD models. Additionally, circRNA nanotherapy has shown efficacy in related retinal conditions such as age-related macular degeneration and diabetic retinopathy. However, translational hurdles, including invasive delivery routes, off-target effects, and regulatory gaps, limit clinical adoption. Nanocarrier-mediated circRNA modulation represents a next-generation strategy for precision therapy in IRDs, with potential to reshape the future of retinal disease management.

Dear Editor,

Inherited retinal dystrophies (IRDs) represent a genetically diverse group of progressive blinding disorders, affecting over 2 million individuals globally. These conditions, including retinitis pigmentosa, Leber congenital amaurosis, and Stargardt disease, are driven by mutations in over 270 genes, leading to photoreceptor apoptosis, dysfunction of the retinal pigment epithelium, and irreversible vision loss^[1]. Patients typically present with nyctalopia, peripheral field constriction, and eventual central vision impairment. Despite advances in gene therapy and retinal prosthetics, curative options remain intangible, particularly for non-RPE65 genotypes and syndromic variants^[2].

Recent breakthroughs in RNA biology and nanotechnology have introduced circular RNAs (circRNAs) as promising therapeutic targets. CircRNAs are stable, non-coding RNA molecules that regulate gene expression via microRNA sponging, protein scaffolding, and transcriptional modulation. Nanocarrier-mediated delivery systems, such as lipid nanoparticles, polymeric micelles, and exosomes, enable targeted, sustained, and minimally immunogenic delivery of circRNA modulators to retinal tissues^[3]. These platforms have demonstrated efficacy in modulating angiogenesis in age-related macular degeneration (AMD), reducing vascular leakage in diabetic retinopathy, and restoring photoreceptor survival pathways in IRDs^[4].

In a recent study by Hanineva et al, lipid-based nanocarriers that deliver synthetic circRNA mimics delayed retinal degeneration and preserved retinal architecture in murine models of retinitis pigmentosa. Complementarily, Mehta et al utilized polymeric nanoparticles to deliver circRNA inhibitors targeting VEGF, resulting in a 65% reduction in neovascularization in AMD models^[1,3,5]. These findings underscore the therapeutic versatility of circRNA modulation and the feasibility of nanocarrier platforms for retinal delivery. However, translation to human IRD therapy remains in early stages, with most data limited to preclinical models.

Despite encouraging preclinical outcomes, several limitations hinder clinical translation. First, the blood-retinal barrier poses a significant obstacle to systemic delivery, necessitating invasive intravitreal injections. Second, off-target effects and immune activation remain concerns, particularly with synthetic circRNA constructs. Third, the heterogeneity of IRDs complicates target selection and necessitates personalized approaches. Moreover, long-term safety, biodistribution, and degradation kinetics of nanocarriers in ocular tissues remain poorly characterized. Regulatory pathways for RNA-based ocular therapies are also underdeveloped, further delaying clinical trials.

To unlock the potential of circRNA nanotherapy in IRDs, future strategies should prioritize non-invasive delivery routes, artificial intelligence (AI)-guided circRNA target prediction, and disease-specific therapeutic libraries. Cost-effective manufacturing and clinician education campaigns will be essential for equitable access. Multicenter trials and longitudinal safety studies are urgently needed to validate efficacy and monitor adverse effects. The convergence of RNA biology, nanomedicine, and retinal genomics offers a transformative path toward precision therapy in inherited retinal disease. This study followed the transparency in the reporting of artificial intelligence (TITAN) guidelines 2025^[6].

Ethical approval

Not applicable.

Consent

Consent for participation and publication is not applicable as this study involves publicly available data.

Sources of funding

The authors received no funding.

Author contributions

E.H: Conceptualization, Methodology, Software, Data curation, Writing – original draft, Writing – review and editing; F.H: Writing – original draft, Writing – review and editing.

Conflicts of interest disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Research registration unique identifying number (UIN)

Not applicable.

Use of generative AI and AI-assisted technologies

No AI or AI-assisted technologies were used in the preparation of this manuscript.