Innovative gene delivery systems for retinal disease therapy
Authors: Wu Hongguang , Dong Ling , Jin Shibo , Zhao Yongwang , Zhu Lili 
Published: December 2024

The human retina, a complex and highly specialized structure, includes multiple cell types that work synergistically to generate and transmit visual signals. However, genetic predisposition or age-related degeneration can lead to retinal damage that severely impairs vision or causes blindness. Treatment options for retinal diseases are limited, and there is an urgent need for innovative therapeutic strategies. Cell and gene therapies are promising because of the efficacy of delivery systems that transport therapeutic genes to targeted retinal cells. Gene delivery systems hold great promise for treating retinal diseases by enabling the targeted delivery of therapeutic genes to affected cells or by converting endogenous cells into functional ones to facilitate nerve regeneration, potentially restoring vision. This review focuses on two principal categories of gene delivery vectors used in the treatment of retinal diseases: viral and non-viral systems. Viral vectors, including lentiviruses and adeno-associated viruses, exploit the innate ability of viruses to infiltrate cells, which is followed by the introduction of therapeutic genetic material into target cells for gene correction. Lentiviruses can accommodate exogenous genes up to 8 kb in length, but their mechanism of integration into the host genome presents insertion mutation risks. Conversely, adeno-associated viruses are safer, as they exist as episomes in the nucleus, yet their limited packaging capacity constrains their application to a narrower spectrum of diseases, which necessitates the exploration of alternative delivery methods. In parallel, progress has also occurred in the development of novel non-viral delivery systems, particularly those based on liposomal technology. Manipulation of the ratios of hydrophilic and hydrophobic molecules within liposomes and the development of new lipid formulations have led to the creation of advanced non-viral vectors. These innovative systems include solid lipid nanoparticles, polymer nanoparticles, dendrimers, polymeric micelles, and polymeric nanoparticles. Compared with their viral counterparts, non-viral delivery systems offer markedly enhanced loading capacities that enable the direct delivery of nucleic acids, mRNA, or protein molecules into cells. This bypasses the need for DNA transcription and processing, which significantly enhances therapeutic efficiency. Nevertheless, the immunogenic potential and accumulation toxicity associated with non-viral particulate systems necessitates continued optimization to reduce adverse effects in vivo. This review explores the various delivery systems for retinal therapies and retinal nerve regeneration, and details the characteristics, advantages, limitations, and clinical applications of each vector type. By systematically outlining these factors, our goal is to guide the selection of the optimal delivery tool for a specific retinal disease, which will enhance treatment efficacy and improve patient outcomes while paving the way for more effective and targeted therapeutic interventions.