INTRODUCTION:

In today’s world, diabetes is the most fatal health issues in relation to mortality rate (1.5 million deaths per year).

Diabetes mellitus (DM) is a metabolic disorder categorized by chronic hyperglycemia, and the most common types are type 1, type 2, and gestational diabetes¹. Numerous organs and organ systems are impacted by diabetes-related conditions. Vascular degeneration is mainly in eyes leads to diabetic retinopathy (DR). Patients with DR range in age from 20 to 65, and symptoms usually appear ten years shortly after diabetes first appears^2,3. It has been assessed that 20 to 30 million people are at high threat of developing DR-related irreversible vision loss, which is at present most leading reason of visual damage and the foremost cause of blindness in preventable retinal diseases^4,5,6,7.

One of the human body's most advanced sense organs, the eye is what gives us vision. Vision creation is made possible by the unique construction and functional coordination of each and every structure (figure 1)⁸.

Figure 1. Schematic diagram of eye

Diabetic retinopathy (DR):

DR is a chronic, progressive retinal vascular condition that has the potential to be blinding⁹. Therefore, DR has the potential to develop into a major hazard that will offer a challenge for healthcare systems going forward as well as a major socioeconomic cost. The therapy and controlling of pathologic ocular neovascularization in the posterior area of the eye in DR is a difficult undertaking because of the anatomical and physiological barriers (figure 2)¹⁰. Pharmacotherapies, early surgical intervention, and laser photocoagulation are the current treatments used to manage DR.. Advanced stages of DR may occasionally require vitrectomy surgery¹¹. Currently, Anti-VEGF (anti-vascular endothelial growth factor) intravitreal injections are utilized in four different ways to treat DR. But these drugs come with a high price tag, require an intrusive procedure, and have a number of systemic and ocular side effects. Repeated injections are sometimes necessary for long-term therapy of chronic diseases like DR, but these injections can lead to serious ocular concerns like endopthalmitis, cataracts, vitreous hemorrhage, and retinal detachment¹². Additional therapeutic approaches for the treatment and management of DR include gene therapy, stem cell therapy, aldose reductase inhibitors (ARI), protein kinase C (PKC) inhibitors, anti-inflammatory agents, inhibitors of carbonic anhydrase, growth hormone inhibitors, renin angiotensin system (RAS) blockers, antioxidants, enzymatic vitreolysis, and combination therapies. However, because to a dearth of safety and effectiveness research, there are just a few therapy options available for the management of DR. Depending on the rigorousness of the disease condition, diabetic retinopathy is divided into two types: proliferative and non-proliferative¹³. There are three levels of non-proliferative DR such as mild, moderate, and severe. If left untreated, the later step can proceed to proliferative DR, which is characterized by visible retinal blood vessel damage. At early phase, blood vessels might grow micro aneurysms, which show swellings look like balloon. It is the second stage of diabetic retinal vein occlusion (DR) and may occur in some of the retina's small blood vessels^14,15. A significant number of microscopic blood vessels clog in severe non-proliferative retinopathy, leading to retinal ischemia—a condition where parts of the retina receive less oxygen¹⁶. The retinal areas responsible for maintaining oxygen levels and stimulating the formation of new blood vessels send electrical signals to the body. Because of their instability and swift breakage, these abnormal blood vessels can quickly cause vitreous haemorrhage, which can cause visual loss¹⁷. Drawbacks of conventional techniques can be addressed with the use of contemporary, revolutionary nanotechnology. At the target site, to enhance and regulate the distribution of ocular therapeutics, either by improving their permeation or by extending contact time through fabrication by encapsulating and administrating small molecules in nanostructured formulation, advanced nanocarrier-based ocular drug delivery systems is being developed. Barriers in the eye prevent pharmaceuticals from being delivered into the posterior portion of the eye, but when a nanosized method is used, they can pass through the barrier for more therapeutic efficacy than when using a traditional technique. Because of their distinct physicochemical characteristics, nanotechnology offers sustained drug release into intraocular tissues via a rapid permeation and retention time, boosting ocular bioavailability even though frequently received dosage form administration is necessary to accomplish better therapeutic efficacy and to sustain therapeutic concentration in intraocular tissues. This analysis sheds light on the many obstacles to ocular drug administration, the approaches being used in treatment, and the latest advancements in nano carrier technology for the management and treatment of DR¹⁸.

Figure 2. Eye affected with diabetic retinopathy

Current scenario:

According to the International Diabetes Federation, in 2019, around 463 million people suffered from diabetes globally and 700 million by 2045¹⁹. One of the primary underlying causes of blindness in working-age individuals is DR, the most dominant and unique consequences of DM (figure 3)^20,21.

Figure 3. Current scenario of blindness: A great challenge

APPLICATION OF NANOMEDICINE:

Nanomedicine in DR could potentially recover current treatments. Factors like size, surface charge, and shape are crucial for developing effective intravitreal injections. Larger carriers improve drug retention and release, while smaller carriers (less than 500 nm size) repress diffusion²². Finally, there are many kinds of approaches of nano particles which could also infiltrate the deeper layers of the retina and help to treat diabetes retinopathy²³. (figure 4).

1. Albumin Nanoparticles: Proteins have been extensively studied as a material for the creation of nanoparticles. Ultimately, albumin is easily able to hybridize with other materials, which facilitates drug trafficking over a variety of biological barriers and increases particle drug encapsulation²⁴.Albumin nanoparticles produced by desolvation and crosslinking to enhance apatinib ocular administration works well as an intravitreal injection of a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor to treat DR. Apatinib's hydrophobic nature has negative consequences, despite its encouraging findings in blocking pathological neo-angiogenesis. For this reason, encapsulation was the method which is used to enhance its solubility, along with, its well-being²⁵. To improve the particle’s ability to interact with mucins, hyaluronic acid (HA) was also applied to them. In this instance, the HA coating promoted the ingestion of the particles by retinal cells that expressed CD44 and enhanced their capacity to disseminate in the vitreous humor. The particles interacted well with mucins and exhibited no toxicity in vitro. They were injected intravitreally or administered topically in vivo. When compared to loaded and uncoated particles, the HA coated loaded particles exhibited stronger anti-angiogenic qualities in both situations. Fluorescence microscopy was used to confirm these findings, which demonstrated increased coated particle retention in the retina. Correspondingly, in another research showed that Polyethylene glycol (PEG) is used as coating agent instead of HA for albumin nanoparticles, to improve their hydrophilicity and biocompatibility. Transepithelial electric resistance measurements revealed an anti-VEGF activity of this apatinib-loaded system in vitro. Intravitreally injected loaded particles prevented the development of edema in a DR model in vivo²⁶.

2. Polymeric Nanoparticles: Natural and Synthetic Polymers: Polymeric nanoparticles can be made from synthetic (poly D, L-lactide-co-glycolide (PLGA)) or natural chitosan molecules. In order to minimize the number of injections required for this medication, evaluation of chitosan was carried out for the intravitreal transport of bevacizumab (anti-VEGF antibody) that was either absorbed on their surface or loaded in the particle core²⁷. As predicted, after two months, equal doses of the encapsulated medication reduced VEGF mRNA expression in comparison to free administered bevacizumab. Anti-Flt1 peptide was delivered into the retina by a new nano formulation based on HA, as reported by Oh et al. It has been demonstrated that HA controls the formation of the retinal capillary network and interacts with a number of receptors expressed in this area, together with CD44²⁸. By comparing the formulation's anti-angiogenic qualities with those of unconjugated particles and observing the micelle's capacity to impede VEGFR1/VEGF binding, the authors demonstrated these properties in vitro. More significantly, in a DR rat model, functionalized micelles showed an improved capacity to diminish the degeneration of retinal neo-angiogenesis in vivo. One of the best practices in polymer nanomedicine is represented by PLGA. To lessen DR degeneration, Qiu et al. fenofibrate was encapsulated in PLGA nanoparticles by Qiu et al²⁹. This treatment is an anti-angiogenic and anti-inflammatory PPAR_ agonist³⁰. Conversely, due to its rapid clearance, conventional oral administration and intravitreal injection are not practical. Fenofibrate's encapsulation in PLGA carriers enabled a regulated release of the medication, which may have reduced the number of injections required. The researchers showed that PLGA was more effective at encasing the medicinal, and that a polyvinyl alcohol coating was used to improve the therapies' dispersibility. The prolonged release of the medication, which persisted for two months in both in vitro and in vivo settings, was further enhanced by the polymer's high molecular weight. In a model of streptozotocin (STZ)-induced diabetic rats, the efficiency of fenofibrate-loaded polymeric carriers was observed to improve retinal function, decrease edema development and inflammatory cytokine release and showed no discernible side effects when compared to empty particles. A comparable technology has been created for the administration of pioglitazone, a PPAR agonist. In this instance, polysorbate 80 was used to the PLGA nanoparticles to improve their contact with the ocular surface and improve topical drug administration³¹. The study investigated drug encapsulation efficiency and release using two lactide to glycolide ratios (75:25 and 50:50). The 75:25 formulation allowed longer pioglitazone release, while the 50:50 formulation reduced VEGF levels in diabetic rats. Polycaprolactone nanoparticles coated with PF68 improved drug release through ocular barriers³².

3. Inorganic Nanoparticles: Inorganic nanoparticles offer stability with anti-angiogenic and anti-inflammatory properties. However, concerns about biocompatibility and product safety limit their use. Silica is widely used for nanocarriers, with personalized biodegradation and FDA approval for food and oral drug additives³³. After topical ocular delivery, the Dr. Park group investigated their toxicity by directly comparing it to the same amounts of swallowed particles³⁴. Scientists found no systemic or organ side effects related to the proposed treatment of patients with a condition, demonstrating anti-angiogenic effects through intravitreally injected silica nanoparticles³⁵. In additional, they demonstrated encouraging outcomes for tacrolimus ocular delivery³⁶. In addition to having strong antiangiogenic properties, silicon nanoparticles were explored to create a theragnostic device for detecting abnormal neo-angiogenesis in the posterior ocular segment³⁷. Gold was demonstrated to possess anti-angiogenic and antioxidant qualities, most likely as a result of its plasmonic characteristics³⁸. Resveratrol served as a stabilizing and reducing agent in the green chemistry synthesis procedure used by Dong et al. to create gold nanoparticles³⁹. Rats were given STZ injections to induce the condition, and for three months, the rats were given calcium dobesilate or gold nanoparticles orally, which are recognized to impede the progression of the ailment. Resveratrol-coated gold nanoparticles demonstrated comparable efficacy to calcium dobesilate in restoring retinal capillaries to their natural state and reducing vascular leakage. Apaolaza et al. utilized gold nanoparticles conjugated with low molecular weight HA to inhibit the development of AGEs and vascular proliferation in various experimental and assay methods⁴⁰. A sorafenib-loaded gold nanoparticle nano formulation was effectively tested to reduce retinopathy in a disease model caused by injection of DL-aminoadipic acid⁴¹. To improve the targeting and biocompatibility of the particles, folic acid coating was applied. Dr. Gurunathan's group proved that silver nanoparticles have anti-angiogenic qualities as well. Particles specifically reduced the Src kinase pathway-mediated in-vitro retinal endothelial penetrability generated by VEGF and IL⁴². To treat DR, octreotide, an analogue of somatostatin, was incorporated into commercial iron oxide nanoparticles⁴³. The anti-angiogenic characteristics of the nano formulation, which was loaded with octreotide by surface functionalization, were demonstrated in vitro in this study. It's interesting to note that the treatment had stronger anti-angiogenic effects when conjugated with the particles than when given to the cells freely.

4. Extracellular Vesicles (EVs) for RNA Delivery: EVs, lipid bilayer nanoparticles, are extensively researched as biologic delivery vehicles^44,45.Delivering short RNAs such as antisense oligonucleotides, microRNAs, and small interfering RNAs (siRNAs) has been the preferred use of EVs in DR. Other strategies rely on EV fusion via extrusion techniques or RNA-loaded liposomes, but usually at the expense of its stability and bio-distribution characteristics⁴⁶. A multitude of miRNAs, including miRNA-20b, miRNA-106a-5p, miRNA-20a-5p, and miRNA-20a-3p, are downregulated in conjunction with the advancement of DR⁴⁷. EVs containing miRNAs can mitigate the effects of high-glucose retinal impairment and inhibit risky angiogenesis associated with diabetic retina progression⁴⁸. When used against DR experimental models in vivo, EVs loaded with miRNA-20a-5p, miRNA-20a-3p, miRNA-222, and miRNA-106a-5p shown notable therapeutic advantages⁴⁹. EVs containing miRNA-202-5p decreased cell proliferation, vascularization migration, and, while EVs containing cPWWP2A and miRNA-579 restored retinal microvascular function^50,51. Adipose-derived EVs loaded with miRNA-192 reduced angiogenesis and inflammation linked to diabetes in rats⁵². MiRNA-21 administration in EVs has been found to alleviate DR retinal degeneration due to its potential to alleviate retinal degeneration, photoreceptor damage, and apoptosis⁵³. EVs generated from adipose stem cells prevented diabetic rabbits' DR deterioration. In experimental diabetic in vivo settings, it was shown that EVs carrying miRNA-222 inhibited aberrant blood vessel formation and restored healthy angiogenesis. EVs with miRNA-126 overexpression in umbilical cord blood MSCs effectively prevented hyperglycaemia-induced inflammation and slowed the onset of diabetic kidney disease in-vivo⁵⁴. Certain miRNAs, such as miRNA-15a, can exacerbate diabetes complications whereas others, like miRNA-15a, can assist DR clinically⁵⁵. Plasma-derived EVs and platelet-rich plasma EVs impact retinal microvasculature and endothelial cells in DR. Long non-coding RNAs can also modify DR development through miRNA-34a-5p and XBP1 axis activity^56,57. Simultaneously, DR cell viability, angiogenesis, and migration were all decreased by short nucleolar RNA host gene 7 (SNHG7)⁵⁶. EV loaded with miRNA-34a-5p may alter the expression of XBP1 and SNHG7, preventing the advancement of DR⁵⁸. The NFIA/NLRP3 pathway may be a potential therapeutic target for DR because it is linked to endothelial dysfunction and microvascular consequences. Circular RNA Ehmt1 was delivered by hypoxia-conditioned pericyte-derived EVs, which inhibited NLRP3-mediated inflammation and increased NFIA expression⁵⁹. New methods for developing DR therapies require sorting miRNAs into EVs, optimizing miRNA release, and increasing cytosolic concentrations following local injection to increase EV application in DR.

5.Lipid-based nanoparticles: Lipid-based nanoparticles (SLN) are developed to overcome the limitations of polymeric nanoparticles, as they are stable at both room and body temperatures. The issue is that lipids are sensitive to the eye, which restricts how they may be used when administering medications to the eyes⁶⁰. Numerous lipids that are generally regarded as safe (GRAS) have been approved by the US along with European Food and Drug Administration⁶¹. These lipids include monoglycerides (glyceryl monosterate), glyceryl palmitostearate, and caprylic and triglycerides⁶². Being composed of physiological lipids, SLN has a longer residence duration, better ocular bioavailability, and no biotoxicity, which is one of its main benefits⁶³. A double emulsion method was employed in a study by Fangueiro et al., 2014 to scatter lipid nanoparticles which are cationic in nature for the trapping of epigallocatechin. Water-derived lipid nanoparticles in an O/W emulsion are hydrophilic drugs, hydrophilic drugs and pliable colloidal carriers for peptide/protein^64,65. HETCAM testing conducted in vitro did not demonstrate any eye pain. In vivo studies on rabbits were conducted to examine pharmacokinetic properties and ocular irritation. Lipid nanoparticles of epigallocatechin have anti-inflammatory and anti-oxidant qualities, which make them useful in the treatment of diabetic retinopathy⁶⁶. It has found that tetrandrine cationic solid-state nanoparticles (SLNs) were synthesized and evaluated for ocular drug administration⁶⁷. The low-temperature emulsion evaporation-solidification method was used to produce cationic SLNs of tetrandrine^{68, 69}. The medicine leaked slowly, according to in vitro drug release assays. Solid lipid nanoparticles showed very little cytotoxicity, according to the cytotoxicity study. Tetrandine-loaded nanoparticles were therefore a more effective method of ocular medication delivery. However, SLNs have several shortcomings due to their inflexible crystalline matrix⁷⁰. Drug molecules in solid lipid nanoparticles (SLNs) typically align themselves within fatty acid chains or glycerides during storage and polymorphism modifications. As a result, medications that were formerly dissolved in solid-liquid nitrogen may undergo eviction at the time of storage⁷¹. Further disadvantages, such as the unpredictable nature of gelation and inherently low integration rates, are attributed to the crystalline form of the solid lipid⁷².

6. Nanostructured lipid carriers (NLC): Liquid and solid lipids, surfactants, and medications comprise NLC. Additional benefits of employing these include enhanced adherence to the ocular surface and sting of non-hydrophobic medicines, which extends residence time of drug's encapsulation and protects it from enzymes degradation⁷³.It has been found that to improve ocular bioavailability, nanostructured lipid carriers (NLCs) containing mangiferin were developed in a study by Liu et al., 2012⁷⁴. Mangiferin is a potent antioxidant⁷⁵. A comparison between pharmacokinetics of mangiferin solution and mangiferin nanostructured lipid carriers showed that the latter had a lower bioavailability (by 5.59 times) than the former. For ocular antiangiogenic applications, a nanostructured lipid carrier loaded with triamcinolone acetonide was developed⁷⁶. Draize eye test demonstrated that NLC preparation that has been refined is safe and does not cause irritation to the ocular tissues. NLCs have certain limitations, like cytotoxic effects on matrix composition and concentration⁷⁷.

7. Dendrimers: Dendrimers are a novel kind of nanoparticles that are synthetic in nature composed of polymers with a highly branched three-dimensional structural tree. Researchers investigated numerous sequences of poly (amidoamine) dendrimers used for controlled administration of ophthalmic medications⁷⁸. The ability of dendrimers to capture poorly water-soluble drugs within their internal voids, the maintenance of a short poly dispersity index along with dendrimer size, prevention of reticuloendothelial system (res) uptake, the enhancement of solubility, retention effect permeability, and the deficiency of cytotoxicity as well as ocular irritation while maintaining targeting proficiency are just a few of the many advantages that dendrimers offer⁷⁹. In case of both normal and DR mouse eyes, the retinal absorption dendrimer combined with cyanine dye (d-cy5) was analysed. The dendrimer uptake was evaluated using immunofluorescence using rabbit iba-1 antibody and a cy3-tagged secondary antibody (microglia/macrophage). Utilizing fluorescence spectroscopy, absorbance in the retina as well as other organs was enumerated. When administered by either way, dendrimers target activated microglia and have a nearly equal distribution throughout the retina⁸⁰.Dendrimers have certain disadvantages such as high costs for synthesis, metabolism, and excretion. Furthermore, insufficient research has been done to determine their cellular toxicity⁸¹. Moreover, the final yield obtained during dendrimer synthesis is frequently insufficient, even when very selective processes are used.

8. Liposomes: Liposomes are tiny, sphere-shaped lipid vesicles made up of cholesterol and phospholipids⁸². Bevacizumab liposomes were produced by Abrishami et al., 2009⁸³. Animal models can be used to study the concentration-time profiles of bevacizumab and bevacizumab liposomes in vitreous humour and aqueous humour. Following forty-two days of continuous observation, bevacizumab liposomes indicated more concentrations in the vitreous humor than formulation without liposomes. It was also found that to treat DR, a formulation of minocycline nanoliposomes was also developed. Systemic minocycline therapy had shown to be efficacious in DR in the rat model by reducing the creation of pro-inflammatory cytokines in the retina and activating microglia. But like more other antibiotics, here is serious risks accompanied with prolong systemic usage. Therefore, the subconjunctival injection of minocycline nanoliposome formulation was a suitable method of administering medication to treat DR by reaching to posterior section of eye. While liposomes have many advantages, they also have several disadvantages, including stability problems and an upsurge in particle size at the time of storage, phagocyte absorption susceptibility, and a short retention period in the retina⁸⁴.Liposomal phospholipids are reactive to oxidation and hydrolysis, both of which can have unfavourable effects. While overcoming these obstacles is necessary to attain the best liposome performance, other aspects, including enhanced permeability and retention (EPR) effect, can be used to boost the delivery of drugs⁸⁵. Thus, it is very evident that Nano medicines have an edge to solve many drawbacks of traditional treatment techniques. Some of the already approved Nano medicines are listed in (Table 1) with details.

CONCLUSION:

A significant complication of diabetes mellitus that lowers a patient's quality of life and increases their risk of blindness is diabetic retinopathy. The old and modern treatment modalities—pharmacological, surgical, and other—are included in this review. The present therapeutic approaches are hindered by non-specific targeting, bioavailability, burst release, and inadequate ocular absorption. Thus, a lot of work has been done by researchers to employ nano-carrier systems to get around some of the drawbacks of traditional treatment techniques. Due to their advantageous characteristics, which include improved penetration, retention, prolonged release, non-invasive form of administration, and targeted efficiency, nanobased approaches have drawn a lot of attention.

Several studies have been published that use lipids and polymeric nanocarriers, among other forms, to improve the bioavailability and ocular penetration of medicinal drugs. Additionally, the nanobased drug delivery system minimizes the frequency of injections and invasive procedures while allowing prolonged drug release. It is versatile enough to accommodate a combination treatment without requiring several procedures. The rapid adoption of ocular nanomedicine will challenge translational and regulatory research but also pave the way for innovative nanotechnology applications in DR pharmacotherapy. Overall, research indicates nanocarrier-based approaches are expected to significantly impact the management of DR in the future, enhancing therapeutic efficiency and patient compliance compared to existing techniques.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

All the authors express their sincere gratitude to the department of Pharmacy of Eminent College of Pharmaceutical Technology and M.R. College of Pharmaceutical Sciences and Research for their support.

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Received on 06.12.2024 Revised on 12.05.2025

Accepted on 06.08.2025 Published on 10.02.2026

Available online from February 16, 2026

Research J. Pharmacy and Technology. 2026;19(2):961-969.

DOI: 10.52711/0974-360X.2026.00136

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

S. No.	Trade Name	API	Nano Carriers	Year of FDA Approval	Marketed By	References
1.	Eylea^®	Aflibercept (VEGF Inhibitor)	Liposome	2011	REGENERON PHARMACEUTICALS	⁸⁶
2.	Leucentis^®	Ranibizumab	Liposome	2017	GENENTECH INC.
3.	Vabysmo^®	Faricinab-svoa	Hydrogel based	2022	GENENTECH INC.
4.	Visudyne^®	Verteporfin	Liposome	2002	QLT INC.