Innovative Gene Delivery Systems for Retinal Disease Therapy

Innovative Approaches in Gene and Cell Therapy

Gene therapy holds promise for treating various retinal diseases by correcting genetic defects or delivering therapeutic genes to restore or enhance retinal function. The human retina is composed of a complex network of neuronal and non-neuronal cells that play critical roles in visual processing. Gene delivery systems are crucial for the effective transport of therapeutic genes to targeted retinal cells. The two principal categories of gene delivery vectors used in retinal therapies include viral vectors, such as adeno-associated viruses (AAV) and lentiviruses, and non-viral systems, such as lipid-based nanoparticles (LNPs) and polymeric carriers.

Viral vectors are particularly advantageous due to their natural ability to penetrate host cell membranes and deliver genetic material efficiently. AAVs, in particular, have gained significant attention because they can effectively transduce retinal cells with minimal immunogenicity (Wu et al., 2024). Lentiviral vectors, on the other hand, can accommodate larger transgenes but may pose risks of insertional mutagenesis due to their integration into the host genome. Non-viral delivery systems, such as LNPs, offer enhanced loading capacities and the ability to deliver nucleic acids, including mRNA and plasmids, without the associated risks of viral vectors (Tawfik et al., 2022; Chen et al., 2023).

Table 1 summarizes the advantages and limitations of various gene delivery systems utilized in retinal therapies.

Mechanisms of Action for Viral and Non-Viral Vectors

Viral Vectors

Viral vectors, especially AAVs, are engineered to deliver therapeutic genes into target retinal cells. AAVs have a single-stranded DNA genome and utilize the natural cellular machinery to integrate into the host genome or remain as episomes, ensuring long-term expression of the therapeutic gene. The tropism of AAVs varies among serotypes, allowing for targeted delivery to specific retinal cell types (Wang et al., 2024).

Lentiviral vectors, derived from retroviruses, can also transduce non-dividing cells, making them suitable for retinal therapy. However, the integration of the viral genome into the host DNA raises concerns regarding mutagenesis.

Non-Viral Vectors

Non-viral vectors, such as lipid nanoparticles, are gaining traction due to their enhanced safety profiles and flexibility. LNPs can encapsulate various nucleic acids, facilitating direct delivery into cells. They work by merging with the cell membrane, allowing their cargo to enter the cytoplasm without integrating into the host genome. This characteristic minimizes the risk of insertional mutagenesis, making non-viral vectors a safer alternative for retinal gene therapy (Zheng et al., 2023).

Role of Antioxidants in Retinal Health and Disease Management

Oxidative stress plays a significant role in the pathogenesis of retinal diseases, including diabetic retinopathy and age-related macular degeneration (AMD). Antioxidants help mitigate oxidative damage by neutralizing reactive oxygen species (ROS) that contribute to cellular injury. Recent studies have highlighted the potential of using antioxidant therapies, such as Cu5.4O nanoparticles, which exhibit excellent biocompatibility and ROS scavenging capabilities, thereby reducing oxidative stress in retinal cells (Zhao et al., 2024).

Understanding the mechanism by which antioxidants function can aid in developing effective treatment strategies for preventing retinal damage. Antioxidants can enhance retinal health by improving mitochondrial function and reducing inflammation, which are crucial for maintaining visual acuity and preventing disease progression.

Impacts of Blood Pressure and Glucose Levels on Retinal Health

Control of blood pressure and blood glucose levels is critical for retinal health. High systolic blood pressure (SBP) and elevated HbA1c levels have been correlated with significant changes in retinal microvascular parameters, particularly in the foveal avascular zone (FAZ) and vessel density (FD-300) surrounding the fovea (Ma et al., 2025).

Table 2 summarizes the findings regarding the correlation of blood pressure and glucose levels with retinal health.

Maintaining optimal blood pressure and glucose levels is essential for preventing retinal microangiopathy and preserving visual function, especially in patients with diabetes and hypertension.

Advances in OCTA Technology for Retinal Disease Diagnosis

Optical coherence tomography angiography (OCTA) has revolutionized the diagnosis and monitoring of retinal diseases. This non-invasive imaging technique allows for the visualization of retinal microvasculature without the need for dye injection. OCTA can quantitatively assess vessel density and analyze changes in the foveal avascular zone (FAZ), providing valuable insights into the underlying pathology of various retinal diseases (Mozafar et al., 2025).

Recent studies utilizing OCTA have demonstrated significant alterations in retinal vasculature in patients with Behcet’s disease, emphasizing the importance of this technology in understanding disease progression and improving management strategies (Mozafar et al., 2025).

Conclusion

The landscape of retinal disease therapy is rapidly evolving with innovative gene delivery systems, addressing the challenges posed by traditional treatment modalities. Viral and non-viral vectors play crucial roles in gene therapy, while antioxidants and effective management of blood pressure and glucose levels are essential for maintaining retinal health. Advances in OCTA technology continue to enhance our understanding of retinal pathologies, paving the way for more targeted and effective interventions.

FAQs

What are the main types of gene delivery systems used in retinal therapies?

• The primary types of gene delivery systems include viral vectors (AAVs and lentiviruses) and non-viral vectors (lipid nanoparticles and polymeric carriers).

How do antioxidants contribute to retinal health?

• Antioxidants help neutralize reactive oxygen species (ROS), reducing oxidative stress and cellular damage in retinal cells, thereby preserving visual function.

Why is controlling blood pressure and glucose levels important for retinal health?

• High blood pressure and elevated glucose levels can lead to microvascular changes in the retina, increasing the risk of diseases such as diabetic retinopathy and AMD.

What is OCTA, and how does it aid in retinal disease diagnosis?

• Optical coherence tomography angiography (OCTA) is a non-invasive imaging technique that allows visualization of retinal microvasculature, enabling assessment of vessel density and changes in the foveal avascular zone.

What are the potential risks associated with viral gene delivery systems?

• Risks include insertional mutagenesis due to integration into the host genome and immunogenicity, which can provoke an immune response against the viral vector.

References

1. Wu, H., Dong, L., Jin, S., Zhao, Y., & Zhu, L. (2024). Innovative gene delivery systems for retinal disease therapy. Neural Regeneration Research. Retrieved from https://pubmed.ncbi.nlm.nih.gov/12220707/

2. Ma, J.-B., Qin, M.-Z., Cao, K., Zhang, Y.-P., & Guo, C.-X. (2025). Control of blood pressure and blood glucose levels has important clinical significance to the retina. BMC Ophthalmology. Retrieved from https://doi.org/10.1186/s12886-025-04164-y

3. Mozafar, M., Amanollahi, M., Samiee, R., Jameie, M., et al. (2025). OCTA measurements in Behcet’s disease across different stages of the disease activity: A systematic review and meta-analysis. PLOS One. Retrieved from https://doi.org/10.1371/journal.pone.0323192

4. Tawfik, M., Chen, F., Goldberg, J. L., & Sabel, B. A. (2022). Nanomedicine and drug delivery to the retina: current status and implications for gene therapy. Naunyn-Schmiedeberg’s Archives of Pharmacology. Retrieved from https://doi.org/10.1007/s00210-022-02287-3

5. Zheng, L., Bandara, S. R., Tan, Z., & Leal, C. (2023). Lipid nanoparticle topology regulates endosomal escape and delivery of RNA to the cytoplasm. Proceedings of the National Academy of Sciences of the United States of America