Diabetes mellitus is a group of diseases characterized by chronic hyperglycemia, and the most common expressions of this condition are type 1, type 2, and gestational diabetes [1]. While type 1 diabetes is an autoimmune disease causing an abnormal immune response against insulin-producing β-cells, significantly blunting the expression of this hormone [2], type 2 [3] and gestational diabetes [4] are also characterized by a certain level of skeletal muscle, liver, and adipose tissue insulin resistance. Genetic, environmental, and behavioral factors, as well as maternal obesity, can cause these conditions. Diabetes incidence is increasing worldwide [5]: the population affected by this disease triplicated in the last 40 years [6], and it keeps on growing [7]. Diabetes-associated conditions affect multiple organs and organ systems, resulting in polyneuropathy [8], angiopathy [9], infections [10], nephropathy [10], dementia [11], cardiovascular complications [12], lower limb amputation [13], and blindness [14]. These phenomena are often irreversible and accompanied by a structural and functional impairment of the tissue microcirculation [15]. Vascular degeneration is particularly prominent in the eye, leading to diabetic retinopathy (DR) [16]. DR affects patients aged between 20 and 65 [17], and its symptoms appear about ten years after diabetes onset [18]. It has been estimated that 20–30 million patients are at risk of irreversible vision loss because of DR [19,20], which is currently one of the leading causes of visual impairment (Figure 1) [21,22,23] and the leading cause of blindness in preventable retinal diseases [24].

DR is caused by a significant retinal and choroidal capillary network degeneration, due to a local chronic inflammation sustained by advanced-glycation end-products (AGEs) [25], reactive oxygen species (ROS) [26], growth factors, and interleukins [27,28].

In DR, the blood–retinal barrier (BRB) becomes highly permeable, causing local edema, necrosis, and ischemic phenomena [29]. The BRB function depends on the integrity and proper conformation of endothelial intercellular junction complexes that are already significantly affected during the first phases of DR. A high vascular endothelial growth factor (VEGF) pathway activity [30] and a misbalance in ROS generation and elimination [31,32,33] induce junction disassembly and leaky blood capillary formation [34]. These phenomena can also affect the protein composition of the vitreous humor [35].

To re-establish the normal tissue vascular flow, a neo-angiogenesis process driven by VEGF expression occurs in the retinal and choroidal tissue [36], potentially causing retinal detachment and vision loss [37].

Clinically, DR is classified in non-proliferative and proliferative DR, and in six stages of retinal degeneration, varying from small bleeding events to significant neovascularization and retinal detachment (Figure 2) [38,39,40]. In addition to structural decline, the stress occurring during DR affects photoreceptor cell function and viability [41].

Optical coherence tomography and fluorescein angiography are commonly used to properly diagnose DR [42], while current therapies for the advanced states of this condition include invasive interventions based on laser photocoagulation (pan-retinal photocoagulation [43]) and vitrectomy [44]. Laser therapy aims at mitigating potential hemorrhagic events by ablating retinal capillary microaneurysms. This procedure requires repetitive applications, and can cause hemorrhages. On the other hand, vitrectomy is a surgical intervention performed to reduce tissue edema and clean the retina from cellular and tissue debris.

Systemic pharmacological treatments [45] aim at lowering blood glucose [46] and lipid [47] levels by adjusting doses and frequency of insulin administration, or administering therapeutics like fenofibrate [48] and statins [49], respectively. In this context also anti-hypertensive therapies [50] showed beneficial properties to mitigate DR progression. However, pharmacological treatments locally administered via subretinal and intravitreal injections are preferred to rapidly and vigorously target the posterior segment of the eye [7].

Typical medications for this disease target the vascular pathologic process and include vascular protective [51] and anti-inflammatory drugs [52,53], angiogenesis inhibitors [54,55,56,57], modulators of the microcirculation [58,59]. More recently, peroxisome proliferator-activated receptor (PPAR) agonists showed beneficial effects in reducing inflammation, normalizing vascular function, and mitigating ROS-associated damages [60]. These therapies can have a heterogeneous patient response, side effects, and sometimes high associated costs [49,61,62,63,64].

In addition, when locally inoculated, they still need to overcome the ocular biological barriers, significantly mitigating their retinal targeting properties, without mentioning the discomfort provoked to the patient by these therapies.

Nanomedicine can provide different benefits to improve DR treatments, increasing therapeutic residence time in the eye and providing controlled drug release. This review will examine different nanoplatforms tested for this purpose, focusing on the material properties that make these technologies attractive for DR. In particular, we focused on technologies designed to normalize vascular degeneration in diabetic retinopathy that represent the primary cause of this disease. A few attempts [65,66,67] to develop nanotechnology for reversing and mitigating diabetic retinopthy neurodegeneration were recently performed, but they do not represent the subject of this review. Article inclusion was performed using Google Scholar and PubMed search engines between august and November 2021. A date sorting filter was applied to include papers not older than five years. To select the included articles, we performed literature research using combinations of the following keywords: diabetic retinopathy; ocular barriers; nanomedicine; polymer nanoparticles; albumin nanoparticles; inorganic nanoparticles; extracellular vesicles.

3. Nanomedicine Application in DR