**1. Introduction**

The human eye is a unique and fragile structure prone to different types of pathologies. It is characterized by an anterior and the posterior segmen<sup>t</sup> [1]. Pupil, cornea, iris, ciliary body, aqueous humor and lens make up the anterior segment, whereas vitreous humor, macula, retina, choroid, and optic nerve are parts of the posterior segmen<sup>t</sup> [1]. The macula is a small area of the retina that contains photoreceptor, special light-sensitive cells, connected to a neuronal network [2]. Retina contains five types of neurons: photoreceptor, bipolar, ganglion, horizontal, and amacrine cells (Figure 1) [3,4]. The retina is the nerve layer that receives visual information, creating impulses that are transmitted through the optic nerve to the visual cortex in the brain [5]. Two types of photoreceptor cells exist: the rods and the cones. It is estimated that there are approximately 120 million rods and about six million cones in the human eye. The unique properties of photoreceptor cells expose them to a variety of genetic and environmental threats. Any dysfunction or deterioration of vital ocular tissue has a dramatic impact on a patient's quality of life. Therefore, the retina is susceptible to several diseases that result in visual loss and blindness. As countries become wealthier and the per capita income increases, prevalence of blindness decreases, and causes of blindness change. In a poor African country, the major of blinding conditions are likely to be cataract and corneal scar. In the middle-income countries such as Latin America, the leading causes of blindness are glaucoma and diabetic retinopathy. Because cataract surgery is more readily available, fewer people become blind from cataract [6]. In wealthy countries,

glaucoma and cataract continue to be very common and important conditions, but most of the blindness is due to retinal degenerative diseases (RDDs) [7], an heterogeneous group of phatologies characterized by progressive death of photoreceptors. RDDs can be caused by defects in proteins involved in photo transduction, synaptic transmission, retinal pigment epithelial (RPE) integrity function, intracellular tra fficking and cilia function. It can be also related to toxic accumulation of retinoids. Each of these RDDs can lead to visual loss or complete blindness [8].

The most common RDDs include age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP). Cytomegalovirus (CMV) retinitis, proliferative vitreoretinopathy, Stargardt disease, and retinoblastoma can also occur and are usually associated with toxic retinoid biogenesis and accumulation [9]. Retinal diseases are already the most common cause of childhood blindness [10] with an incidence of 1.5 million people su ffering worldwide. RP is characterized by a progressive loss of photoreceptors and its specific mechanisms are not fully understood. Following the loss of photoreceptor functionality, a retinal remodeling phenomenon is triggered as the final step, which then culminates with cell death and topological restructuring of the retina. The progression of retinal remodeling is similar to negative plasticity that occurs in some pathologies like trauma and epilepsy constituting substantial impediments to rescue strategies of all types [11]. Another process that involve the retina segmen<sup>t</sup> is neovascularization, a pathological phenomenon that provokes vision loss causing blindness due to its correlation with diabetic retinopathy and AMD [12]. In the neovascularization phenomenon, endothelial growth factor (VEGF) pathway has a key role [13,14].

Ocular diseases, and retinal diseases in particular, are still approached using rather invasive treatments, which are also not completely e ffective. The development of e fficacious therapeutics is thus a primary research goal. So far, many delivery strategies have been explored, and the progress in the field of molecular genetics has led to the identification of genes involved in retinal disruption. For this reason, gene delivery systems represent one of the most promising approaches [15,16]. Delivery approaches can be broadly classified in two groups, whether they are based on a viral or non-viral method of delivery. Each system comes with advantages and disadvantages. For instance, although Adeno-Associated Virus (AAV) based vectors have high gene transduction e fficiency, they face a major obstacle in terms of biosafety for clinical applications. The development of e ffective non-viral approaches for ocular disease is thus crucial. However, how to adequately deliver therapeutic agents to the back of eye (i.e., retina) remains a challenge. With the development of nanotechnology and bioengineering science, a wide range of innovations in this area have been achieved. This holds the promise for developing more e ffective ocular drug delivery systems.

In this review, we carefully report the last studies in which noble metal and soft (bioinspired) NPs were applied as new delivery agents for treatment of ocular disease in vitro and in vivo. We also provide perspective on opportunities and challenges for future nanotechnology in retinal drug delivery and therapies.

**Figure 1.** Retinal neuronal and vascular structure and retinal disease. (**A**) Diagram of a human eye. Light passes through the pupil and is focused by lens onto macula of the retinal layer at the back of the eye. (**B**) Retina consists of three layers of neurons, photoreceptor, bipolar, and ganglion cells. The retinal pigment epithelial (RPE) monolayer together with Bruch's membrane (BM) form outer blood retinal barrier that separates the neuroretina from the choroid. Choroidal circulation provides oxygen and nutrients to outer retina. (**C**) The retina has an interconnected network of three vascular layers located in the ganglion cell/nerve fiber layer, inner plexiform layer (IPL), and outer plexiform layer (OPL). (**D**) retinal tissue and cells that are affected under different disease conditions. Adapted from reference [17].
