Nanomedicine: Transforming the Management of Ocular Neuroinflammatory and Neurodegenerative Diseases

Abstract

Nanomedicine is emerging as a groundbreaking strategy for the management of the neuro-visual symptoms of neuroinflammatory and neurodegenerative diseases. This innovative field of study leverages nanoscale materials and technologies to improve drug delivery, enabling targeted treatments to reach the affected ocular tissues. By facilitating the transport of therapeutic agents across the blood–retinal barrier and boosting their bioavailability, nanomedicine holds the potential to significantly mitigate the symptoms of conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), etc. This review summarizes the latest developments in nanomedicine applications for the management of these ocular conditions, highlighting their capacity to foster more effective disease diagnosis and treatment.

1. Introduction

Nanomedicine, the integration of nanotechnology into medical applications, has opened new frontiers in managing ophthalmic neurodegenerative and neuroinflammatory diseases. These diseases, which include conditions like Alzheimer’s disease, Parkinson’s disease, multiple sclerosis (MS), and ocular myasthenia gravis (OMG), often involve progressive damage to the nervous system and inflammation that can compromise vision and overall ocular health. Neurodegenerative diseases result in the loss of neuronal function, leading to irreversible damage, while neuroinflammatory diseases trigger immune-mediated inflammation that can harm the delicate structures of the eye. The complexity of these conditions poses significant challenges to effective diagnosis and treatment [1].

As illustrated in the Figure 1, a major challenge in treating these disorders is the different anatomical and protective barriers of the eyes, including the blood–retinal barrier (BRB), which regulates the exchange of substances between the bloodstream and the retina. This barrier protects the ocular layers from substances that are hazardous for the eye, but at the same time limits drug delivery. Similarly, the blood–aqueous barrier (BAB) is another defensive barrier of the eye, limiting the passage of unwanted compounds from the systemic circulation. The cornea, the conjunctiva, and the sclera serve as physical and chemical barriers that further hinder the penetration of therapeutic agents. Traditional drug delivery systems often fail to achieve therapeutic concentrations in the posterior segment of the eye, leading to suboptimal treatment outcomes. These limitations are particularly critical in chronic conditions, where prolonged drug delivery and consistent therapeutic levels are required [2].

Conventional treatments for ocular symptoms in neurodegenerative and neuroinflammatory diseases like AD, PD, and myasthenia gravis are often ineffective due to poor bioavailability, limited blood–ocular barrier penetration, and the rapid clearance of topical drugs. Systemic therapies do not adequately target ocular complications, and frequent eye drop use leads to low retention and poor patient adherence. Nanomedicine offers a breakthrough solution by using nanoparticles and liposomes to enhance drug delivery, improve penetration, provide sustained release, and enable precise targeting, ultimately improving treatment efficacy and patient outcomes.

Without a doubt, nanomedicine offers a promising solution to these challenges by leveraging nanocarriers like liposomes, dendrimers, and polymeric nanoparticles. These nanocarriers can be designed to bypass ocular barriers, enhance drug stability, and enable targeted delivery to specific tissues. For instance, nanoparticles can penetrate the BRB, allowing the direct delivery of neuroprotective agents to retinal neurons. Furthermore, the use of surface modifications such as PEGylation can improve the biocompatibility and circulation time of these nanocarriers, ensuring sustained therapeutic effects. This is particularly valuable in addressing the progressive nature of neurodegenerative and neuroinflammatory diseases, where early and consistent intervention is critical [3].

The potential of nanomedicine extends beyond drug delivery to include diagnostic applications. As illustrated in Figure 1, multiple nanotechnology-based imaging techniques, such as quantum dots and nano-enabled biomarkers, enable the early detection and monitoring of disease progression. These theranostic approaches combine therapy and diagnostics, paving the way for personalized treatment strategies that are both effective and minimally invasive. However, challenges such as potential nanocarrier toxicity, immunogenicity, and the need for regulatory approvals must be addressed to ensure safe and successful clinical translation.

The growing burden of ophthalmic neurodegenerative and neuroinflammatory diseases, compounded by the limitations of conventional treatments, underscores the need for innovative approaches like nanomedicine. By addressing the barriers to drug delivery and enabling precision medicine, nanotechnology holds immense promise in transforming the management of these complex disorders.

Treating ocular symptoms in neuroinflammatory and neurodegenerative diseases is essential because these conditions often lead to progressive vision impairment, affecting daily functioning, independence, and overall quality of life. Ocular complications, such as blurred vision, dry eye, and impaired eye movement, can contribute to difficulties in reading, driving, and balance, increasing the risk of falls and social isolation. Additionally, visual dysfunction may serve as an early marker of disease progression, making effective treatment crucial for both symptom management and potential early intervention. However, conventional therapies often fail to adequately address these issues due to poor drug delivery and limited ocular penetration. Advancing targeted treatments, particularly through nanomedicine, can enhance therapeutic outcomes, improve patient quality of life, and provide new avenues for managing these debilitating diseases. The current study summarizes the latest developments in nanotechnology-based applications for the management of a range of neuro-ocular conditions, highlighting their capacity to foster more effective disease diagnosis and treatment solutions [1].

2. Different Neuro-Ophthalmological Manifestations and the Contribution of Nanomedicine

This section of the paper provides an overview of the symptomatology associated with major neurodegenerative and neuroinflammatory diseases. By examining the common and distinct symptoms of these conditions, we aim to highlight the ways in which they affect the nervous system and, in turn, influence overall health and quality of life. As shown in the summary table below (

Table 1. Summary table with the main neuroimmune and neurodegenerative disease and their ocular symptomatology [4,5].

Disease Category	Disease Name	Ocular Symptoms
Primary Headache Disorders	Migraines	Eye flashes, “foggy” vision, bright zig-zag lines or dots, scotoma, and aura.
Neuroimmune diseases	Multiple Sclerosis	Uveitis, retinal atrophy, inflammatory-mediated optic nerve injuries, retinal peri phlebitis, optic disc atrophy, and slits in the retinal nerve fiber.
Neuroimmune diseases	Ocular Myasthenia Gravis	Cranial nerve palsies, gaze palsies, internuclear ophthalmoplegia, blepharospasm, and stroke.
Neurodegenerative Diseases	Alzheimer’s Disease	Problems in the visual field, decreased contrast sensitivity, color defects, eye flashes, ocular movement abnormalities, disorientation, and visual hallucinations.
Neurodegenerative Diseases	Parkinson’s disease	Visual field disturbances, dry eye symptoms, color vision abnormalities, altered contrast sensitivity, visual hallucinations, vision loss, asthenopia.

), understanding the clinical manifestations of a range of neurodegenerative and neuroinflammatory diseases is essential for improving early diagnosis, patient management, and treatment strategies. Through this exploration, we will also lay the groundwork for discussing how emerging therapies, including nanomedicine, can address these challenges.

2.1. Primary Headache Disorders

The term “primary headache disorders” refers to conditions without an unknown underlying cause. This disease category includes various types of migraines and headaches with a range of neuro-ophthalmic complications [4].

2.1.1. Migraines

Migraine is the most common type of primary headache disease, including a range of rarer, related conditions. The prevalence of the disease is almost 15% of the adult populations of the Western world. The increased prevalence of the disease worldwide, in combination with the acute pain and devastating neurological symptoms of the condition, has a significant social impact in the modern world [4].

During migraine attacks, the trigeminovascular system (TGVS) is activated triggering vasoactive neurotransmitter release from the nerve cells, causing vascular changes, neuroinflammation, and pain [6]. In fact, this neuronal complex consists of nerve cells mainly from the ocular system and is a critical pain-signaling pathway of the brain, responsible for the innervation of the cerebral vasculature [6,7].

There are multiple migraine categories; the two main ones are migraine without aura (MWA) and migraine with aura (MA). The onsets of MWA and MA are separated into different phases that may occur independently or in combination. There are four phases, the prodrome phase, the aural phase (only in MA), the headache phase, and the postdrome phase [5]. It must be mentioned that even MWA patients may exhibit abnormalities in visual field testing, especially during migraine episodes [4].

The many ophthalmological complications that are related to MA include eye flashes, “foggy” vision, bright zig-zag lines or dots, scotoma, and aura. Almost 30% of MA patients experience aura, a localized neurological condition responsible for primarily visual but also sensory, verbal, and motor symptoms right after the end of the prodrome phase [4]. Recent studies have shown that there is a very high risk of ischemic stroke in patients with MA [8]. Aura can be found also in retinal migraine, a less common retinal disorder characterized by scotoma or vision loss in only one of the eyes and headache. The primary cause of the disease is ischemia or arterial narrowing inside or behind the affected eye [9].

Non-steroidal anti-inflammatory medicines (NSAIDs) or aspirin can be used as a preventative measure, not to cure aura, but rather to prevent or eliminate the headache phase. In cases where the headache is not avoided, tryptamine-based drugs can be used for the management of the condition [8]. Unfortunately, the efficacy of these preventive therapies is limited, with most of them having serious side effects. Thus, there is an urgent need for the development of new and efficient anti-migraine preventative treatments [10].

2.1.2. Migraine Diagnosis

Currently, several neuroimaging modalities can be used for a better understanding of the neurological and biological processes that take place during a migraine-attack. For example, functional MRI (fMRI) and PET studies have enabled the identification of major migraine-related functional events.

Functional MRI studies have led to the identification of various brain areas (e.g., red nucleus, substantia nigra, cerebellum, thalamus) that are activated during a migraine episode. Also, fMRI studies have exhibited an elevation in the blood oxygen level-dependent (BOLD) signal during migraine aura. Similarly, PET scanning has shown the local activation of brain areas like the dorsal pons, medulla, and the cerebellum. Additionally, PET analysis can prove the reduced blood flow levels in the occipital, temporal, and parietal lobes, during aura migraine [11].

2.1.3. Nanotechnology-Based Treatment of Migraine

The scientific community is actively exploring innovative nanotechnology-based approaches for the management of migraines. Conventional migraine treatments often face limitations, such as delayed onset of action, inadequate targeting, and undesirable side effects. Nanotechnology has the potential to overcome these challenges by enabling more efficient drug delivery systems, which can provide faster and more precise targeting of therapeutic agents to the affected areas.

The drug sumatriptan succinate is the first FDA-approved drug for the treatment of acute migraine. It is a 5-hydroxytryptamine receptor agonist, able to bypass (to some extent) the blood–brain barrier (BBB). Even though it bypasses the BBB, there is no effective oral drug delivery system that successfully targets the brain.

Earlier studies have depicted that chitosan biopolymers improved the brain uptake potential of hydrophilic drugs including sumatriptan succinate. In their study in 2015, G.P. Hansraj et al. developed injectable sumatriptan succinate-loaded SLNs, modified with chitosan, for maximum drug entrapment capacity, better brain targeting, and sustained in vitro sumatriptan succinate release [12].

A year later, P. Girotra et al. developed zolmitriptan (Zol)-loaded PLGA/poloxamer NPs for the management of ocular migraine. In vivo studies demonstrated a 13-fold increase in brain uptake potential, compared to the free drug injections. Meta-analysis studies confirmed the delivery efficacy of the drug formulation to the brain of albino mice though crossing the BBB and highlighted the anti-migraine capacity of the formulation [13]. Another study on the anti-depressant drug zolmitriptan improved the systemic bioavailability and the brain targeting capacity of Zol-loaded solid lipid nanoparticles (SLNs) gel for the treatment of migraine [14].

Finally, a common physiological phenomenon during migraine aura is the depolarization of glial and neuronal cells. This neurophysiological event regulates the activation of matrix metalloproteinase-9 (MMP-9), triggering neuroinflammation. Some studies utilized superparamagnetic iron oxide NPs as an indirect way of identifying the BBB regions that malfunction during migraine-induced neuroinflammation. Various immune cells, like microglia and macrophages, take up these injectable nano-formulations increasing MMP-9 levels, confirming neurogenic inflammation [15].

Nanotechnology-based solutions are essential for enhancing migraine treatment, as they address the limitations of traditional therapies, such as delayed onset, poor bioavailability, and side effects. Various types of nano-formulations, including superparamagnetic iron oxide NPs and PLGA formulations, improve drug delivery by providing faster, more targeted relief and better blood–brain barrier penetration. These formulations also allow for controlled, sustained release, reducing the need for frequent dosing and minimizing adverse effects [12].

2.2. Neuroimmune Diseases

Autoimmune disorders (AIDs) are mainly caused by the loss of immunological tolerance to self-antigens. There are more than a hundred AIDs, and some of them affect directly or indirectly the host’s nervous system. Some AIDs, including thyroid eye disease (TED), multiple sclerosis (MS) and myasthenia gravis (MG), exhibit a wide range of neuro-ophthalmologic manifestations.

AIDs incidence rates are exponentially growing in the developing world, making them a severe healthcare problem. Traditionally, immunosuppressive drugs and non-disease-specific therapies are being used for the management of AIDs, despite their long-term side effects. Therefore, novel therapeutic approaches are required to help AIDS patients regain self-tolerance in a safe and long-lasting way [16].

2.2.1. Ocular Manifestations in Multiple Sclerosis (MS)

Multiple sclerosis (MS) is the most common neuroinflammatory disease of the central nervous system (CNS), with the worldwide prevalence reaching 2.3 million [17,18]. Recent epidemiological data support that the prevalence of the disease is remarkably higher in females, and in young people less than 35 years old. Even though the etiology of the disease is still unclear, various genetic and environmental factors are thought to be related to the onset of the disease [17].

Chronic inflammation, glial hyperproliferation, axonal demyelination, neuronal degeneration, and immune infiltration are some of the main histopathological hallmarks of the diseases. These changes in the CNS are responsible for a series of pathological problems including visual aberration, loss of coordination, and severe muscle weakness [17]. A range of ocular-related symptoms like optic nerve degeneration, partial or total vision loss, and diplopia can be observed during the early stages of the disease [19].

There are three main MS subtypes, categorized based on the clinical course of the disease (Figure 2). The first sub-category is the relapsing/remitting MS (RRMS), which represents approximately 80% of the worldwide cases. This category is characterized by flare relapses accompanied by remission periods. RRMS patients commonly shift to secondary progressive MS (SPMS), which is characterized by fewer relapses and symptomatology progression. Another major MS subtype is the primary progressive MS (PPMS), which represents 10% of the total cases, and is classified as a constant disease worsening right after the onset of the condition, but without any relapsing periods [17,19].

2.2.2. MS Immunopathophysiology of MS

The major steps in the development of MS are the robust deregulation of the host’s immunity, stimulating an immunological attack on the protective myelin sheath surrounding the neurons. This autoimmune attack triggers a cascade of pathological events including demyelination, axonal loss, oligodendrocyte damage, inflammation, neurodegeneration, and the emergence of sclerotic plaques. These inflammatory lesions are concentrated within the white matter, primarily affecting the basal ganglia, the brainstem, the spinal cord, and the visual neurons.

All the above play an important role in hindering neural signaling, since white matter neurons are responsible for the transmission of electrical impulses within the brain and the rest of the body [17].

Various studies have supported the relationship of various neurological conditions with ocular abnormalities. Focusing on MS, the anterior visual tract is a common target of abnormal inflammatory changes, leading to uveitis, retinal atrophy, inflammatory-mediated optic nerve injuries, retinal periphlebitis, optic disc atrophy, and slits in the retinal nerve fiber [18]. Recent epidemiological data have shown that one in five MS patients suffer from inflammatory-induced optic nerve injuries of the anterior visual tract [20].

It is widely accepted that optic neuritis is a major ophthalmological presentation of MS, which affects almost 25% of MS patients worldwide. Nevertheless, a wide range of ocular manifestations arise during MS, depending on the exact location of these neuroinflammatory plaques [21].

MS-related uveitis is another ophthalmological condition that is currently exercising the scientific world. In general, uveitis refers to the inflammation of the uveal tract and other ocular tissues like the retina and the optic nerve. Recent epidemiological data have suggested that MS-related uveitis is mostly found in RRMS cases, and sometimes in PPMS cases. A study in early 2020 by P. Casselman et al. investigated the common genetic background of MS and uveitis. Firstly, the nervous and the ocular tissues are derived from the same neural ectoderm layer. Additionally, both conditions are closely related to the expression of HLA antigens, responsible for lymphocyte hyperproliferation and inflammation [22].

A study of A. Green et al. highlighted the connection of inflammation with retinal degeneration in MS patients, with a 17-fold higher prevalence of retinal atrophy. Most of the time, retinal atrophy was accompanied by the neuronal degeneration of the inner nuclear layer and retinal ganglion cells. Additionally, immunohistochemical analysis proved that inflammatory mediators, monocytes, and phagocytes were found to be nearby retinal veins surrounding the retinal nerves as well as the retinal ganglion cells, indicating localized inflammation. Similarly, glial fibrillary acidic protein staining showed a large-scale astrocytic hypertrophy and gliosis targeting the inner retina and the optic disc, proving the extensive pathophysiological changes seen in the eyes of MS patients [20].

Another study by E. Graham et al. described the term vision “floaters” in MS patients, which are mainly caused by inflammatory cells present in the gel-like fluid that fills up the eyes. In the same study, fluorescein angiography in MS patients demonstrated extensive vascular leakage in retinal layers [23].

It must be mentioned that various medical imaging modalities like optical coherence tomography (OCT) and MRI can be used for the identification of pathophysiological changes like retinal nerve degeneration and retinal ganglion cell loss. Recent studies have supported that through OCT it may be feasible to predict the disease progression, as well as the ophthalmological issues that may arise. OCT angiography is a specialized imaging modality that can be used in MS research and patient monitoring [24].

2.2.3. Nanomedicine-Based Diagnosis and Therapy of MS

It is widely accepted that MS is a complex disorder, involving the malfunction of peripheral and central immune cells; therefore, therapies must act on both levels [25]. The currently available MS therapies focus on slowing down the disease progression, through managing abnormal processes like axonal demyelination, immune response inhibition, and seizure of inflammation [19].

The utilization of nanoscale formulations offers a tremendous advance in drug bioavailability and solubility, enabling a more targeted and controlled drug release with minimum side effects. These novel structures have gained the attention of scientists, since they can act as vectors and deliver important genes, molecules, or drugs to the target side; therefore, they can regulate immune responses [25].

Recent studies have suggested that nanomaterials can mimic the properties of extracellular vesicles (EV) that are naturally released by the cells. Natural EVs are clinically important biomarkers of neurodegeneration and physiological cell-to-cell communication systems, making them ideal therapeutic candidates of various neurological diseases including MS.

Researchers have led the development of artificial vesicles (Art-Vs) made up of artificial membranes that sustain the characteristic structure of EVs. In the aqueous core of Art-Vs, hydrophilic and charged molecules can be encapsulated, while in the outermost lipid bilayer, hydrophobic and non-polar drugs can be encapsulated.

The first type of Art-Vs that was manufactured by scientists were the liposomes. These nano-formulations were then combined with various cell-penetrating factors to increase their permeability and drug accumulation within the MS lesions. Many liposomal applications involve the encapsulation of antigenic myelin peptides to induce immune tolerance effects.

Various studies have shown that liposomes loaded with a range of myelin basic protein (MBP) peptides ameliorated the phenotype of experimental autoimmune encephalomyelitis (EAE) models of MS and eased the recovery from the acute disease phase. Other studies have investigated the role of MBP fragments in the activation of the immune system through the secretion of immune cells like cytokines [25].

Additionally, FDA-approved nano-sterically stabilized liposomes (nSSLs) functionalized with glucocorticoids improved the recovery effect of the nano-formulations in EAE models [25]. A study of Schweingruber and his team examined the possible anti-inflammatory effects of glucocorticoid-loaded liposomes through the inhibition of T-cell apoptosis. Another study demonstrated that prednisolone-loaded liposomes reinstated BBB integrity, minimized inflammation macrophage infiltration into the CNS, slowing down MS progression in vivo. Surface functionalization of glucocorticoid-liposomes with glutathione enabled the targeted delivery of the nano-formulation to the brain of EAE models [26]. Similarly, pegylated liposomal structures loaded with steroidal drugs like prednisolone and methylprednisolone were found to be useful in ameliorating the clinical picture of EAE models, compared to free drug-delivery experiments [25]. PS-liposomes loaded with MS autoantigens were found to be recognized be phagocytic cells inducing immune tolerance in EAE models [26]. More specifically, these nano-formulations were engulfed by dendritic cells, modulating immune responses through the inhibition of autoimmune interactions. Also, nanoliposomes loaded with 2-10H-indole-30-carbonyl)-thiazole-4-carboxylic acid methyl ester) (ITE) and disease-specific antigenic peptides suppress MS in vivo, through antigen-specific interactions [25].

Similarly, polymers, metals, and other natural and synthetic materials can be used for the formulation of NPs that may serve an important role in the treatment of MS. To start with, poly (lactic-coglycolic acid) (PLGA) nanoparticles loaded with myelin antigens were found to be able to induce immune tolerance through dendritic cell regulation, in RR-EAE in vivo models. Other nano-formulations combined myelin antigens with immunomodulatory drugs, triggering a more effective and targeted immune reaction. Subcutaneous injections of PLGA NPs loaded with MS autoantigens and interleukin-10 (IL-10) ameliorated the disease phenotype in EAE models. In a similar way, PLGA-rapamycin PLGA NPs loaded with autoantigens interacted with macrophages, inducing antigen-specific T-regulatory cell proliferation and transgenic T-cell inhibition. Similarly, leukemia inhibitory factor (LIF)-loaded PLGA particles promoted oligodendrocyte maturation though pSTAT-3 signaling in vitro and improved the thickness of the myelin sheath as well as the percentage of the myelinated axons in vivo [25].

Another example is the myelin oligodendrocyte glycoprotein (MOG)-PLGA-NPs and the proteolipid protein (PLP)-PLGA NPs found to drastically inhibit MS symptomatology in EAE mice, ameliorating the phenotype of the animals. In a similar way, in vitro experiments with PLGA NPS loaded with MS relevant peptides reduced the inflammatory processes of phagocytes and inhibited the proliferation of T cells inducing cell apoptosis [26].

Another type of NPs that are currently under investigation for the treatment of MS are the solid lipid nanoparticles (SLNs). These nanoscale structures can bypass the BBB and transfer therapeutic molecules to the CNS. Dimethyl fumarate (DMF)-loaded SLNs functionalized with vitamins, tocopherol acetate cholecalciferol, and retinol acetate ameliorated the clinical picture of in vivo EAE models stimulating axonal remyelination. Also, PEGylated SLNs loaded with anti-contactin-2 or anti-neurofascin antigens increased brain accumulation compared to naked SLNs [25]. Dimethyl fumarate (DMF) is an FDA-approved anti-inflammatory drug for the treatment of MS. Unfortunately, due to the low brain permeability of the drug, high and frequent dosing is required, promoting a range of adverse effects. Currently, scientists are trying to encapsulate DMF in SLN systems to increase the half-life and bioavailability of the drug in vivo [26].

Chitosan-NPs loaded with the siRNA of a protein that inhibits axonal myelination (LINGO-1 protein) stimulate demyelination in vivo. This nano-formulation downregulates LINGO-1 function, stimulates MBP transcription and translation, and reduces caspase-3 expression levels, stimulating axonal remyelination and neuroprotection. Finally, hybrid organic–inorganic NP formulations strongly react against human phagocytes in EAE models, especially when combined with glucocorticoid drugs.

Nanotechnology-based solutions are crucial for managing the ocular symptoms of MS due to their ability to address major challenges in drug delivery and treatment efficacy. MS-related ocular symptoms, such as optic neuritis, blurred vision, and double vision, are often difficult to treat with conventional therapies due to poor bioavailability, limited penetration of the blood–retina barrier, and rapid drug clearance. Nanocarriers, including liposomes, nanoparticles, and dendrimers, can improve drug delivery by enhancing stability, allowing for more effective targeting of the eye. For example, liposomal formulations can protect drugs from degradation and enable controlled release, reducing the frequency of dosing. Nanoparticles also allow for sustained, localized drug delivery, which minimizes systemic side effects and enhances therapeutic precision. Furthermore, nanotechnology can be used to encapsulate multiple therapeutic agents, offering a multi-target approach to managing both ocular and neurological symptoms of MS. By improving the bioavailability, targeting, and sustained release of drugs, nanomedicine not only enhances the management of ocular symptoms but also helps in improving patient adherence, reducing the burden of treatment, and ultimately improving patient outcomes [25].

2.3. Ocular Myasthenia Gravis (OMG)

Generalized myasthenia gravis (GMG) is an autoimmune disease that mainly affects the neuro–muscular junctions (NMJs) found in the musculoskeletal system, promoting severe muscle weakness. The major affected areas include the muscles around the eyes, the throat, and the lower extremities.

The classification of the disease is highly dependent on the type of clinical characteristics and the type of autoantibodies involved in each case [27]. Ocular myasthenia gravis (OMG) is a sub-category of GMG, presenting extensive ophthalmological symptomatology including cranial nerve palsies, gaze palsies, internuclear ophthalmoplegia, blepharospasm, and stroke [28].

2.3.1. MG Pathophysiology

To start with, the NMJs are responsible for the mechanical and chemical communication of nerve fiber with muscle cell through neurotransmitter release, resulting in the transmission of nerve impulses to the muscle cells [28]. Under physiological conditions, the rapid changes in the voltage at the terminal end of the nerve fiber promote the opening of the voltage-gated calcium channels, triggering the subsequent release of the neurotransmitter acetylcholine (ACh) in the synapsis. The binding of ACh molecules on the neurotransmitter-specific receptors unblocks the sodium channels, promoting muscle contraction. Under pathological conditions, ACh autoantibodies bind effectively to ACh-specific receptors, blocking the physiological neurotransmitter transmission, increasing normal ACh internalization and turnover, or activating the complement system [27].

2.3.2. Ophthalmological Features of MG

Often, MG patients exhibit several ophthalmological manifestations either during the presentation of the disease or during disease progression. During the initial stages of the disease, one in two patients exhibit ptosis and diplopia.

Specifically, eyelid manifestations including ptosis are a predominant sign of the disease onset, that can be either unilateral or bilateral. Another eyelid-related clinical sign is Cogan’s lid twitch. The patient must maintain a downward gaze for 15 s, then gaze rapidly upwards and then return to the primary gaze position. Other lid-related manifestations include unilateral eyelid retraction (contralateral ptosis) as well as the orbicularis weakness, where the eyelids tend to move apart, revealing the underlying sclera.

Extraocular muscle-related manifestations, including diplopia, are a common sign of the disease which is mostly accompanied by ptosis. Additionally, OMG patients can also less often display hypometric large saccades or hypermetric small saccades, intrasaccadic fatigue, reduced saccadic velocity, and nystagmus [28].

2.3.3. Current Diagnosis and Treatment of OMG

The table below (

Table 2. Currently available tests used in the diagnosis of MG [28].

Test Name	Test Type	General Details
Sleep Test	Test in the clinic	Observing the re-appearance of MG signs like ptosis (within 5 min), after a 30 min sleep.
Ice Test	Test in the clinic	Application of an icepack on the patient’s eyelid, and measurement of the change in ocular motility and ptosis.
Electromyogram (EMG)	Test in the clinic	A nerve is electrically stimulated, and the muscle responses are measured through EMG.
Edrophonium Test	Pharmacological Test	Blocks acetylcholinesterase function in the NMJs, preventing ACh breakdown.
Neostigmine Test	Pharmacological Test	An alternative to the edrophonium testing, with a better duration of action.
AChR antibodies	Pharmacological Test	Diagnostic “Gold Standard”, high levels of AChR Abs confirm MG diagnosis.
Anti-MuSK antibodies	Immunological Testing	Mainly used for seronegative MG-patients.
Brain MRI	Immunological Testing	Identification of structural brain stem lesions related to MG.

) summarizes the main tests that are currently available for the diagnosis of OMG. In fact, some of them must be performed by the physicians in the clinic (e.g., sleep test, ice test), some of them are laboratory-based (e.g., AChR Ab testing) and some of them are pharmacological tests (e.g., edrophonium test) [28].

In general, patients must start their treatment plan early, right after the classification of subtype. The available treatment plans aim to minimize muscle weakness thus improving the ophthalmological signs of diplopia and ptosis [27]. For example, acetylcholinesterase inhibitors can be used to improve the classical symptomatology of the disease, through elevation of the ACh levels. Also, the inflammatory properties of corticosteroid drugs can limit the expression of cytokines and the differentiation of lymphocytes. Additionally, corticosteroids modulate AChR synthesis in the muscle fibers, being responsible for the greatest response in OMG patients. Several side effects of the corticosteroid drugs include acne, obesity, hypertension, diabetes, osteoporosis, and steroid-induced myopathy.

Additionally, immunosuppressive drugs like azathioprine, cyclosporine A, and mycophenolate mofetil (MMF) can be used to pharmacologically diminish the host’s immune responses. Bone marrow and liver toxicity are some of the major adverse events that can be related to various immunosuppressive therapies.

Again, plasmapheresis can be used for the management of acute and severe muscle weakness in MG, through the reduction in AChR Ab levels in the serum of the patients. Lastly, intravenous immunoglobulin injections (IVIG) can be used to speed up the IgG catabolism, inhibit the production of antibodies, and block the activation of the complement cascade. However, the use of IVIG injections is limited to the perioperative period, and sometimes for the management of myasthenic crisis [28].

2.3.4. OMG and Nanomedicine

The multiple advantages of liposomes including their safety, biocompatibility, biodegradability, and reproducibility made them a rigid candidate for drug delivery applications.

Various liposomal platforms have been extensively used to assess the efficacy of a range of drugs and active compounds, in the treatment of autoimmune diseases. These nano-liposomal formulations were studied in vivo with disease-specific experimental animal models. For example, anti-inflammatory drugs have been delivered to assess their therapeutic efficacy in rheumatoid arthritis (RA) and type 1 diabetes mellitus experimental models. Also, PS-rich liposomes loaded with autoantigens are being tested on neuromyelitis optica animal models. A single change in the encapsulated autoantigen is enough to obtain a novel and completely different formulation that may be used in the future in clinical practice.

Even though MG pathogenesis is clearly known in detail, the available therapeutic drugs are surprisingly unspecific [27]. To upgrade the immunotherapy platform described by Almenara Fuentes et al. last year and evaluate the therapeutic potential of the platform in OMG patients, disease-specific nanoparticles were developed. MG-specific autoantigens, like AChR peptides, were encapsulated in phosphatidylserine (PS)-rich liposomes biomimicking apoptotic cells. These nano-formulations were assessed both in vitro and in vivo for their efficacy in re-establishing self-tolerance. As shown, upon the administration of AChR-loaded PS-liposomes, they were evenly distributed to the target, engulfed by macrophages and other phagocytic cells, stimulating an interaction with the immune system, influencing self-tolerance and immunogenicity [16].

2.4. Neurodegenerative Diseases

Neurodegenerative disorders (NDs) are currently the biggest threat to the global public health system. NDs are the primary cause of disability-adjusted life-years (DALYs) and the second leading cause of death especially in the western populations [29].

The diagnosis and treatment of ND disorders like Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease is a major challenge for modern medicine. Different therapeutic approaches have been used over the past few decades, but only symptomatic treatment has succeeded.

2.4.1. Alzheimer’s Disease (AD)

Alzheimer’s disease (AD) is an age-related ND characterized by memory loss, cognitive decline, and mood swings [30]. It is the most common dementia subtype, affecting one in three people in the developed countries [31]. Scientists support the idea that AD-related neurodegenerative changes alter various ocular physiological functions including saccade movement, eye-tracking, and pupillary responses [32].

The histopathological hallmarks of the disease include the intracellular senile amyloid plaques, and the extracellular neurofibrillary tangles (NFTs) made of the hyperphosphorylated protein tau. These cerebral structures have been proven to precede AD symptomatology. Recent findings support the progression of the disease in the neurosensory regions of the brain and the retinas [33].

The retina is characterized as the developmental extension of the CNS, connected through the optic nerve. These interconnected parts of the brain are highly affected by degenerative alterations in AD. Interestingly, the retina is the sole region of the CNS that can be non-invasively imaged. Visual examination of AD patients revealed problems in the visual field, decreased contrast sensitivity, color defects, eye flashes, as well as ocular movement abnormalities, disorientation, and visual hallucinations [30].

Early studies have proved the presence of these AD-related histopathological structures in the postmortem retinas of AD patients. Other studies have highlighted the tremendous degeneration of RGCs and neuronal cells, as well as astrogliosis in the superior and inferior retinal regions. Recent studies have proved the presence of soluble Aβ oligomers in the retinas of in vivo AD animal models, suggesting their possible presence in the human retinas as well.

A recent study of Konoyo Yosef et al. revealed the relationship of intraneuronal amyloid deposits and oligomers with retinal macrogliosis, microgliosis, and retinal atrophy, which suggest an interconnection between retinal and brain AD pathophysiology. In the same study, proteosome analysis revealed the various activations of neuroinflammatory mediators like the major histocompatibility complex and the superoxide dismutase type 1 (SOD1) in the retinal region, and the simultaneous downregulation of major photoreceptor-markers like peripherin-2 and rhodopsin.

The retina renders direct and affordable access as well as non-invasive visualization and temporal monitoring of various immunological targets. For example, non-invasive retinal optical imaging has been extensively utilized for the detection of senile plaques, retinal atrophy, and vascular damage in vivo [33]. Another interesting technological advancement is the newly developed non-invasive OCT angiography (OCTA), enabling the detailed visualization of the retinal vasculature, the exact size and shape of the retinal cells, as well as the blood flow in the ocular capillaries. As a result, vascular changes in AD patient retinas can be efficiently visualized, making this device a vital tool for early disease detection [31]

Despite the advance of retinal imaging modalities and the identification of the neuro–retinal region as a site of AD pathology, more research must be performed to fill the remaining gaps regarding the AD-related retinal pathology [33].

Nanomedicine and AD

Recently, a vast array of nanomedicine tools have been developed to improve drug targeting and drug delivery to difficult-to-reach areas like the brain. As illustrated in Figure 3, polymeric NPs, lipid NPs, and metal-based NPs are extensively being used in the field of neurodegeneration and dementia, serving as promising tools for the diagnosis and treatment of such disorders.

Nanoparticles can be used to encapsulate and protect various chemical moieties, minimizing the potential cytotoxicity side effects that may arise from their delivery. Additionally, NPS influences the solubility, the stability, the biodistribution, and the pharmacokinetics of a drug or chemical structure.

Currently, state-of-art nanodevices have been designed to enlighten AD diagnosis. For example, nanodevices specific for the identification of Aβ peptide of amyloid plaques are being used for disease diagnosis. Chemically modified SPIONs combined with MRI have been used for the diagnosis of AD-related biomarkers in vitro, in vivo, and ex vivo. In a similar way, gadolinium- and ET6-21-modified liposomal structures have been developed and combined to medical imaging to enable amyloid-targeting ligand. Another interesting hybrid nanodevice has been developed through graphene oxide and magnetic nanoparticles to detect the two major proteinic complexes involved in AD. Again, tau and amyloid beta antibodies have been linked to the outer surface of the nanodevice promoting antibody–antigen conjugation.

To overcome any possible limitations of drug administration to the CNS (e.g., accessibility issues, decreased drug solubility, limited stability, high molecular weight) drug-loaded nano formulations are currently being examined for their therapeutic efficacy. Lipid-based NPs (LNPs) are commonly used for the delivery of active substances due to their safety, biocompatibility, biodegradability, and versatility. For example, in vitro experiments with α-bisabolol LNPs protected the neuro-2a cells, by impeding the aggregation of amyloid monomers. A similar neuroprotective action has been observed with curcumin-loaded LNPs in vivo. Another interesting study examined the possible antioxidant effects of pomegranate extract (PE)-loaded LNPs in vivo. A remarkable reduction in the NFTs and amyloid plaques has been observed in the treated animals, compared to the untreated controls. Finally, erythropoietin (EPO) gained the attention of the scientists due to their contribution in neuronal survival and neurogenesis. EPO-loaded SLNs reduced the amyloid load and the production of ROS in rat models, and EPO-loaded LNPs showed an amelioration in spatial memory [34].

Polymeric nanoparticles (PNPs) are another common type of drug delivery system, due to their extensive versatility, increased loading capacity, and the ease of modification and fabrication. PNPs can be designed as vesicular structures (nano-capsules) or sphere surface (nanospheres). Some of the most used polymers in the pharmaceutical industry are the polylactide (PLA), the poly(lactide-co-glycolide) (PLGA), the chitosan, the polyethyleneimine (PEI), and the poly-ε-caprolactone (PCL). For example, lutein-loaded PLGA PNPs, modified with chitosan sugar molecules, exhibited a significant ROS scavenging activity in vitro. Additionally, curcumin-loaded PLGA PNPs, modified with the BBB penetrating peptide K16ApoE, improved BBB transcytosis and MRI contrast. Vitamin D-Protein (DBP)-loaded PNPs prolonged the calculation of the glycoprotein in the blood, inhibiting amyloid polymerization and accumulation both in vivo and in vitro, and hence minimizing neuroinflammation and neurodegeneration. Encapsulation of the neuroprotective peptide NAP in PNPs reduced ROS production, minimized neuroinflammation and microtubule disruption, as well as tau aggregation and neurodegeneration in AD animal models [35]. Similarly, a study of Zhang et al. demonstrated the remarkable increase in bevacizumab bioavailability when administered encapsulated in PLGA NPs, during in situ ocular angiogenesis therapy [36]. Bevacizumab is an FDA-approved recombinant monoclonal antibody, which acts as an angiogenic stimulator for the treatment of ocular neurovascular diseases [35].

Metal-based NPs (MNPs) are another nanomedicine-based tool, due to their high surface area and ease of functionalization with different antibodies, genes, and peptides. These nanocarriers are commonly developed with gold, silver, iron, zinc, and copper, and have strong anti-microbial, anti-inflammatory, and antioxidant properties. For example, quercetin-modified gold NPs triggered amyloid clearance by autophagy, limiting amyloid-induced neurotoxicity. In a similar way, a multi-targeted approach using the antioxidants, chondroitin sulfate and selenium, were used to assess their protective effect against amyloid toxicity. This multi-targeted approach highlighted the importance of these antioxidants in neuronal regeneration, axonal growth, synaptic plasticity, as well as detoxification, inhibition of amyloid-induced cell apoptosis, immunoregulation, and redox homeostasis. Another study of Sonawane et al. assessed the effect of iron oxide and cadmium sulfide MNPs in tau-related pathogenesis. Both MNP types exhibited a strong inhibition of tau aggregation and NFT dissociation in vitro.

Going a step further, in 2020, ultrasmall superparamagnetic iron oxide NPs (USPIONs) combined with a near-infrared (NIR) fluorescent dye were developed for both AD diagnosis and treatment. The ultra-small amyloid proteins tend to accumulate on the USPIONs, minimizing the amyloid load in the bloodstream and inhibiting amyloid aggregation. Interestingly, a fluorescence signal is emitted upon binding of the amyloid proteins on the USPIONs [34]. Similarly, carbon dots (CTs) are a novel nanotechnology-based theranostic tool, with remarkable physicochemical, therapeutic, and optical properties. Polymerized o-phenylenediamine (pOPD)-derived CTs inhibited amyloid protein fibrillation and aggregation alleviating ROS production, and oxidative stress-induced neuronal degeneration in vitro. Finally, recent studies on nanotechnology-based devices have highlighted the strong binding capacity of nanoplasmonic fiber tip probes (nFTP) made up of metal nanorods, to toxic amyloid fibrils and tau monomers, leading to the detection of AD histopathological hallmarks through inverted microscopy and spectrometry in vitro. Another electrochemical nanoprobe made up of horseradish peroxidase (HRP), gelsolin, and Au-NPs were used for the evaluation of the amyloid load in normal and diseased animal models. Interestingly, novel dye-sensitized NPs were excited by near infrared light at 800 nm, to evaluate their possible utilization in deep tissue imaging in vivo, and at the same time, led to neuronal activation and neurogenesis without any signs of damage.

As we can see, nanotechnology-based solutions are essential for managing AD ocular symptomatology due to their ability to overcome significant challenges in drug delivery. Conventional treatments often struggle with poor bioavailability, limited penetration across the blood–retina barrier, and rapid drug clearance, which can hinder the effective treatment of ocular manifestations. Nanocarriers, such as nanoparticles and liposomes, enable the more precise and targeted delivery of therapeutic agents to the eye, enhancing drug stability and bioavailability. Additionally, nanomedicine offers controlled release, which reduces the frequency of dosing and minimizes side effects by ensuring drugs are delivered directly to the affected areas. By addressing the limitations of traditional treatments, nanotechnology can improve treatment efficacy, reduce systemic exposure, and offer more effective management of ocular symptoms in AD. More studies need to be performed to clarify the exact mode-of-action of nanomaterials during disease diagnosis and treatment [27].

2.4.2. Parkinson’s Disease (PD)

Parkinson’s disease (PD) is one of the fastest growing neurodegenerative disorders worldwide [37]. Normal aging is the number one risk factor for the development of the disease, followed by mutations in the high-risk genes, environmental toxins, smoking, and industrialization [37,38].

The disease symptomatology includes problems with cognition and depression, apathy, sleep disturbance, as well as dementia, autonomic, and sensory problems. The sensory problems can comprise visual field disturbances, dry eye symptoms, color vision abnormalities, altered contrast sensitivity, visual hallucinations, and in more severe cases, vision loss [39,40]. Additionally, more than 43% of PD patients develop asthenopia, which is the most common visual complication of the disease [39]. Unfortunately, these vision complications are frequently missed during PD basic neuro-ophthalmological examination but are currently considered as some of the initial symptoms of the condition [41].

PD is characterized by insufficiency in the neurotransmitter dopamine, leading to motor and non-motor aberrations including ocular problems [39]. Dopamine may be involved in major physiological processes including the organization of ganglia and the regulation of photoreceptor cells [40]. Also, recent studies have shown that dopamine depletion in the cerebral cortex is highly associated with various vision problems including color vision problems, adaptation to the light, diplopia, and oculomotor disturbances. It is important to mention that some dopaminergic medications used may have vision-related adverse effects, like hallucinations, levodopa-induced eye movement disorders, and blurring vision [41].

The two main dopamine transmission circuits are the striatal pathway starting from the substantia nigra to the cerebral cortex, and another one starting from the ventral tegmentum to the anterior region of the cortex. There are some minor dopaminergic pathways in the hypothalamic region of the brain as well, boosting further the neurotransmitter activity in the frontal region of the cortex. Considering this, a much lower dopamine activity can be observed in the vision-related regions of the brain.

The major histopathological hallmark of the disease is the characteristic inclusions called Lewy bodies (LB) found in the substantia nigra and cortex of the brain. These cytoplasmic inclusions are mainly derived from filaments of the cytoskeleton and contain abnormal forms of the α-synuclein protein [40].

It is crucial to develop targeted and effective therapeutic options as well as brand new treatment plans to eliminate the burden of the condition [38].

Nanomedicine and PD

Despite the presence of multiple therapeutic options, the treatment of the disease is still palliative, requiring contemporary alternatives. A major obstacle in the treatment of the disease is the BBB and its ability to prevent the passage of substances, including drugs. Additionally, current therapies are mostly non-specific and are taken in doses that cause many unwanted consequences.

Nanotechnology-based interventions have emerged as a potential therapeutic strategy for the treatment of various neurologic conditions including PD. Among the available types of nano-formulations, lipid nanoparticles (LNPs) possess a series of advantages, including their lipophilic nature, their increased brain permeability, bioavailability, and biodegradability as well as their limited toxicity, and ease of modification. Also, their valuable ability to be conjugated with a range of active substances makes them one of the most promising therapeutic approaches that will reach the clinic.

A research team in 2020 used ropinirole (RP)-functionalized LNPs, a well-known dopamine agonist exhibiting an improved pharmacokinetic profile, compared to oral and topical drug administration. The same study showed a remarkable reduction in oxidative stress and peroxidation levels. Another team in 2021 utilized an albumin/PLGA nanoparticle, functionalized with dopamine molecules. The nano-formulation efficiently bypassed the BBB and reached the brain cells through specific receptors. As a result, dopamine ameliorated the disease symptomatology including motor coordination and sensorimotor cognition (e.g., vision) in vivo. Similarly, liposomes modified with the dopamine derivative N-3,4-bis(pivaloyloxy)-dopamine, boosted cellular uptake by endothelial and dopaminergic cells though better BBB penetration, enhancing therapeutic efficacy. Importantly, in 2021, a phase 1 clinical trial was started, which evaluates the therapeutic efficacy of liposomal nano-formulation loaded with the drug Talineuren [42].

Moving on to polymeric nanoparticles, the initial approach for the use of polymers in dopamine delivery was carried out by Pillay et al. in 2009. The controlled release of these nano-formulations were tests both in vitro and in vivo, exhibiting very promising results. In a later stage, the same team injected these nanostructures into the brain parenchyma of a rat model, to assess a possible alternative route of administration. A few years later, Trapani et al. developed chitosan-functionalized polymer-based nanoparticles to assess their cytotoxicity effects in vitro, promoting an improved cytotoxicity profile and dose-dependent increase in neurotransmitter output. More recent studies have tried to further functionalize the formulations, through the addition of esters and amides, to improve dopamine transport through the BBB. Also, dopamine-loaded PLGA NPs were tested with SH-SY5Y cells, without affecting cell viability. When tested in vivo though intravenous injections, the nanostructures efficiently bypassed the BBB, reducing PD symptomatology, ROS production, and neuronal degeneration. More recent studies have used albumin to achieve even BBB permeability through receptor-mediated endocytosis again, improving motor coordination, balance, and sensorimotor performance in vivo.

Inorganic nanocomposites are another type of drug delivery system, due to their low cytotoxicity, increased bioavailability, ease of functionalization, and remarkable biocompatibility, making them the ideal candidate for targeted delivery approaches. For example, AuNPs have been used to evaluate the dopamine-loading efficiency of peptidoglycan monomer-coated AuNPs, suggesting the possible use of these nanostructures for the treatment of dopamine-related diseases. Additionally, semiconducting NPs like QDs exhibit some unique optoelectronic and fluorescence properties. A study carried out by Malvindi et al. led to the development of fluorescent marker PEG-cadmium selenide/cadmium sulfide QDs for dopamine-controlled release. Similarly, in 2020, CS-carbon QDs exhibited >80% dopamine encapsulation efficiency neurotransmitter-sustained release. However, it would be crucial to assess further in vitro and in vivo the effectiveness of these tools, especially in the sensorimotor area [43].

3. Insight into Ophthalmic Symptoms in Neurodegenerative and Neuroimmune Diseases

Nanotechnology refers to the application of materials and devices smaller than 100 nanometers in size [44]. Recent advances in material science, nanomedicine, nano-chemistry, and nanobiotechnology have paved the way for new pharmaceuticals, implantable materials (like tissue regeneration scaffolds), implantable devices, and diagnostic tools (like intraocular pressure sensors), which are revolutionizing modern medicine [2,44].

The first documented application of nanotechnology in ophthalmological treatment dates to 1995 when Zimmer and Kreuter investigated nanoparticles and microspheres for ocular drug delivery. Nearly two decades later, Mudgil et al. highlighted the advantages of nano-systems, including better specificity, enhanced bioavailability, and reduced drug dosage requirements. Their research also emphasized the potential of biodegradable polymers such as poly (lactic-co-glycolic acid) (PLGA) and poly(epsilon-caprolactone) (PCL), alongside natural polymers like chitosan and albumin, in ocular drug delivery applications. In 2013, Ye et al. compared conventional and nanotechnology-based drug delivery systems, identifying the limitations of traditional drugs, including poor aqueous stability, reduced solubility, and a risk of ocular irritation [44].

Nanomedicine has emerged as a promising avenue for the treatment of various neurological and ocular disorders, including migraines, autoimmune diseases like multiple sclerosis (MS) and ocular myasthenia gravis (OMG), as well as degenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Starting with migraines, these complex conditions are characterized by severe headaches and other severe ophthalmologic-related symptoms like foggy vision and aura. Traditional treatments often have limited efficacy and sometimes may cause severe side effects [4]. Nanotechnology offers potential benefits in this area by enabling targeted drug delivery systems that can cross the blood–brain barrier (BBB) more effectively. For instance, the nanoparticle-based delivery of anti-migraine medications could enhance therapeutic outcomes while minimizing systemic side effects. However, specific studies focusing on nanomedicine applications in migraine treatment are still in the early stages, and more research is needed to establish efficacy and safety.

Moving on to autoimmune disease, MS is characterized by demyelination in the central nervous system. Nanomedicine approaches have been explored to modulate immune responses and promote remyelination. For example, gold nanoparticles have been investigated for their potential to reverse metabolic deficits in MS patients, offering a novel therapeutic strategy [14]. Additionally, OMG is another common autoimmune disorder which mainly affects the NMJs, leading to muscle degeneration in the eyes [27]. While specific nanomedicine applications for OMG are still under investigation, the principles of targeted drug delivery using nanoparticles hold promises for improving treatment efficacy and reducing systemic side effects in autoimmune ocular conditions [16].

Finally, degenerative diseases are common especially in the aging population. For example, AD is the most common age-related degenerative condition worldwide, characterized by the accumulation of amyloid-beta plaques and tau tangles leading to neurodegeneration. Nanoparticle-based delivery systems have been developed to transport therapeutic agents across the BBB, aiming to reduce plaque formation and promote neuronal survival. Studies have demonstrated that polymeric nanoparticles can effectively deliver drugs that inhibit amyloid-beta aggregation, potentially slowing disease progression [45]. Also, PD, the second leading cause of degeneration worldwide, involves the degeneration of dopaminergic neurons. Nanocarriers, such as gold nanoparticles, have been investigated for their ability to deliver neuroprotective agents directly to the central nervous system. Recent clinical trials have shown that gold nanocrystals can improve the brain energy metabolism in PD patients, suggesting potential therapeutic benefits [46].

Despite these advances, challenges remain in the clinical translation of nanomedicine for neurological disorders. Concerns regarding long-term safety, potential immunogenicity, and the scalability of manufacturing processes need to be addressed. Additionally, the regulatory landscape for nanomedicines is still evolving, necessitating comprehensive studies to establish their efficacy and safety profiles [47].

Safety and Toxicity Issues

Despite its numerous advantages, the application of nanomedicine comes with safety concerns, including the potential for oxidative stress, cytotoxicity, genotoxicity, neurotoxicity, and immune responses.

Protective barriers in the eye do not always prevent smaller nanocarriers from penetrating deep ocular layers, leading to accumulation in the retina. The retina, composed of multiple neuronal layers and retinal ganglion cells (RGCs), is particularly vulnerable to oxidative stress and neurotoxicity, which can result in neurodegeneration. Nanoparticles (NPs) capable of crossing the blood–brain barrier (BBB) may also induce cytotoxic effects or immune activation.

One of the primary mechanisms of neurotoxicity is the production of reactive oxygen species (ROS). For instance, titanium dioxide (TiO₂) NPs increase intracellular ROS levels in neurons and microglia. Silica NPs induce a phagocytic response in microglia, elevating both ROS and reactive nitrogen species. Similarly, hydroxylated fullerene NPs are associated with cytotoxicity and phototoxicity in retinal cells [48].

Other studies have revealed that certain nano-formulations can penetrate epithelial barriers and reduce cell viability. Quantum dots (QDs), for example, significantly decrease corneal stromal cell viability at low concentrations (5–20 nM) and may persist in the cornea for up to 26 days, potentially causing apoptosis, neurodegeneration, and corneal damage via ferroptosis. Conversely, nano-emulsions (NE) are generally safe at concentrations below 1% but can reduce cell viability at higher doses [49].

Nanomaterials can also provoke immune responses. Gold nanoparticles (Au NPs) activate immune pathways involving toll-like receptor 2, granulocyte macrophage colony-stimulating factor, and interleukin 1-alpha. Silver nanoparticles (Ag NPs) disrupt neuronal spikes and inhibit voltage-gated sodium channels.

Gene expression alterations have also been linked to certain nanomaterials. For instance, manganese and copper nanoparticles affect dopamine-related gene expression. Cobalt ferrite NPs increase ROS production and the activity of antioxidant enzymes such as catalase and glutathione S-transferase [48]. Studies on zebrafish exposed to low concentrations of Ag NPs indicate developmental abnormalities in the lens and changes in gene expression related to lens formation. Additionally, Ag NPs can cause DNA damage, chromosomal aberrations, and cell cycle arrest at very low concentrations [49].

Inflammatory responses are another concern. Nanomaterials like dendrimers, carbon nanotubes, liposomes, and TiO₂ NPs have been linked to strong inflammatory and allergic reactions in both animal models and humans.

The toxicity of nanoparticles in ocular and CNS tissues is influenced by factors such as concentration, solubility, dose, size, shape, and surface charge. For example, smaller silica NPs cause dose-dependent microglial death, whereas larger silica NPs do not. Similarly, small copper NPs exhibit significant toxicity even at low concentrations. This heightened toxicity may be due to the larger surface area of smaller NPs, which facilitates stronger interactions with cellular environments. In some cases, toxicity depends on concentration rather than size. For instance, zinc oxide (ZnO) NPs induce cytotoxicity across various sizes (10 nm to 200 nm) based on their concentration.

The surface charge and functionalization of nanoparticles also influence toxicity. Positively charged nano-systems tend to have higher cellular uptake, increasing the likelihood of toxicity. For example, cationic gold NPs exhibit significant changes in cell viability compared to their anionic counterparts. Hydroxyl-modified PAMAM dendrimers demonstrate reduced neurotoxicity and inflammation in vivo but require careful consideration of drug-loading capacities to maintain efficacy without com-promising safety.

Time is another critical factor. Functionalized nanoparticles may alter biodistribution and prolong their presence in retinal compartments, leading to localized toxicity. In rare cases, PLGA polymers fail to degrade fully, accumulating in the eye due to factors like material purity, manufacturing processes, and solvent residues [50].

In summary, the design of nanocarriers should carefully balance factors such as size, surface chemistry, charge, and drug-loading capacities to minimize toxicity and promote safe clinical applications [48,50].

4. Conclusions

Derived from the Greek word for “nano”, nanotechnology has applications across various fields, including engineering, physics, electronics, and molecular-level manufacturing [44]. In ophthalmology, it has the potential to revolutionize traditional practices by enabling advancements in drug therapy, gene therapy, medical imaging, and drug discovery [2,44].

Nanotechnology has driven the development of innovative drug delivery systems and diagnostic tools using nanoparticles, liposomes, and dendrimers. These nano-formulations possess unique physicochemical properties due to their high surface area-to-volume ratio, making them highly versatile in various biomedical applications [44].

However, despite significant progress, challenges remain in addressing neuroinflammatory and neurodegenerative conditions. These disorders often present significant challenges, such as poor drug bioavailability, limited blood–brain barrier penetration, and suboptimal therapeutic efficacy. By utilizing advanced nanocarriers, researchers are developing innovative approaches that offer more targeted, sustained, and effective treatments while reducing systemic side effects and improving patient outcomes. The unique biochemistry of the eye further complicates pharmacokinetics, making many active substances ineffective [51]. Traditional treatment methods often result in poor bioavailability, short drug residence times, and significant side effects. To overcome these challenges, researchers have modified the size, shape, and surface properties of nanocarriers, such as through PEGylation or altering the surface charge, to improve drug delivery [52].

Nanomedicine offers a transformative approach to the management of complex neurological disorders, including migraines, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and ocular myasthenia gravis. By enhancing targeted drug delivery and improving therapeutic efficacy, nanotechnology-based interventions have the potential to overcome the limitations of conventional treatments. A key example is migraine treatment, where nanotechnology is being explored to optimize brain-targeted drug delivery. Sumatriptan, an FDA-approved migraine medication, has been incorporated into nano formulations to enhance its ability to cross the blood–brain barrier, leading to faster relief, prolonged therapeutic action, and reduced side effects compared to traditional formulations. This advance is crucial, as migraines can severely impact quality of life, and current treatments often fall short in providing long-lasting relief. In MS, nanotechnology is making strides in both diagnosis and treatment. Scientists are investigating the use of natural extracellular vesicles as a non-invasive diagnostic tool, capable of carrying disease-specific biomarkers for earlier and more accurate detection. On the therapeutic side, FDA-approved drugs like dimethyl fumarate (DMF) are being encapsulated in nanocarriers to improve their bioavailability, half-life, and targeted delivery. This approach minimizes systemic toxicity and enhances drug efficacy, providing a more efficient and patient-friendly alternative to conventional MS therapies. For AD, nanotechnology is improving both early diagnosis and disease-modifying treatments. Chemically modified superparamagnetic SPIONs are being utilized in MRI imaging to enhance contrast and enable earlier, more precise detection of AD-related brain changes. Additionally, drug-loaded liposomal and polymeric nano formulations are being developed to inhibit key pathological mechanisms of the disease, such as amyloid-beta aggregation and oxidative stress caused by ROS. These targeted interventions not only aid in early diagnosis but also offer neuroprotective effects that could slow disease progression. Beyond individual diseases, nanotechnology-based solutions using lipid nanoparticles, polymeric nanoparticles, and inorganic nanocomposites are revolutionizing drug delivery by improving pharmacokinetics and pharmacodynamics. Encapsulating therapeutic agents in these nanocarriers enhances drug stability, ensures controlled and sustained release, and increases precision in targeting affected tissues. These advancements reduce side effects, improve treatment efficacy, and offer new possibilities for managing complex neurological conditions [52].

Ongoing research and interdisciplinary collaboration are essential to address existing challenges and fully realize the potential of nanomedicine in neurology. As the field progresses, it is anticipated that nanotechnology-based therapies will become integral components of standard care for these debilitating conditions, offering hope for improved patient outcomes. By addressing the fundamental challenges of drug delivery and disease detection, nanomedicine provides a powerful tool for the effective management of neurodegenerative and neuroinflammatory disorders. These innovations have the potential to enhance patient care, increase treatment success rates, and pave the way for more personalized and efficient therapeutic strategies in the future [53].

However, despite these promising developments, significant challenges remain. Concerns related to the long-term safety, potential toxicity, immunogenicity, and the precise mechanisms of nanomaterial interactions within the body must be thoroughly addressed. Moreover, the regulatory frameworks governing nanomedicine require refinement to ensure the successful translation of research findings into clinical applications.

To unlock the full potential of nanomedicine, a substantial investment in interdisciplinary research is essential. Future studies must focus on optimizing nanoparticle design, improving scalability and reproducibility in manufacturing, and conducting large-scale clinical trials to validate safety and efficacy. By fostering collaboration among researchers, clinicians, and regulatory bodies, nanotechnology can advance into a new era of precision medicine, offering hope for the effective management of previously untreatable neurodegenerative and ocular conditions [54].