Nanoparticle-Based Strategies to Enhance Catecholaminergic Drug Delivery for Neuropsychiatric Disorders: Advances, Challenges, and Therapeutic Opportunities

Abstract

Background/Objectives: Neuropsychiatric disorders such as Parkinson’s disease, depression, and Alzheimer’s disease are characterized by deficits in catecholaminergic neurotransmission. Conventional pharmacotherapies have several limitations, including poor blood–brain barrier permeability, rapid peripheral metabolism, systemic toxicity, and suboptimal brain bioavailability. This review evaluates nanoparticle-based strategies that can overcome these limitations by enhancing the delivery of catecholaminergic drugs to the central nervous system (CNS). Methods: A narrative synthesis was conducted based on a comprehensive review of research articles published by July 2025. Articles were retrieved from PubMed, Scopus, and Web of Science. The studies examined nanoformulations of catecholaminergic agents with a focus on CNS delivery, BBB penetration, toxicity, and therapeutic outcomes in neuropsychiatric disease models. Results: Evidence shows that nanoparticle platforms can stabilize drugs and extend their release time. They can also enable BBB penetration. These platforms reduce peripheral side effects and improve behavioral and neurochemical outcomes in preclinical models. Conclusions: Nanoparticles are a promising strategy for optimizing pharmacotherapy for CNS disorders associated with catecholamine deficiencies. However, more research is needed on their long-term safety, bioaccumulation, and clinical feasibility before they can be widely adopted.

1. Introduction

Biogenic amines are a class of neurotransmitters that are produced naturally by the body. Examples include norepinephrine (NE) and dopamine (DA). These molecules are essential for normal brain function and are involved in processes such as mood regulation, attention, learning, memory, reward, and motor control. Biogenic amines are synthesized from amino acid precursors and operate through tightly regulated pathways that ensure synaptic balance and neuronal communication. Even slight disruptions in their levels or signaling can lead to significant cognitive, emotional, and behavioral dysfunctions [1,2,3].

Imbalances in biogenic amine levels have been linked to various neurological and psychiatric disorders. For instance, the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to motor impairments, such as bradykinesia, muscle rigidity, and resting tremors, which are characteristic of Parkinson’s disease [4]. Similarly, alterations in the cholinergic system are a hallmark of Alzheimer’s disease [5]. However, biogenic amines, such as NE and serotonin, are also disrupted [4]. These alterations contribute to cognitive decline, mood disturbances, and behavioral symptoms. Major depressive disorder (MDD) is characterized by low levels of serotonin, NE, and DA, leading to a persistently low mood, anhedonia, and cognitive impairment. These neurotransmitter imbalances affect various brain regions, including the prefrontal cortex, limbic system, and basal ganglia [6]. Due to the severity, complexity, and high prevalence of these conditions, neuropsychiatric research and drug development for decades have focused on restoring neurotransmitter balance through pharmacological interventions [7].

Several classes of drugs have been developed, including selective serotonin reuptake inhibitors (SSRIs), DA precursors such as levodopa (L-DOPA), and monoamine oxidase inhibitors (MAOIs) [8,9]. However, these drugs have significant limitations. These limitations include poor specificity, systemic side effects, rapid development of tolerance, and, critically, low brain bioavailability due to the restrictive nature of the blood–brain barrier (BBB) [10]. While the BBB protects the brain from harmful substances, it also limits the entry of most therapeutics, reducing their efficacy and complicating disease management [11]. Consequently, many patients experience incomplete symptom relief or adverse reactions, underscoring the urgent need for more effective, targeted therapeutic delivery systems.

In recent years, nanotechnology has emerged as a promising strategy for overcoming these challenges. Nanoparticles (NPs), which typically range from one to 100 nanometers in size, can be engineered to cross the BBB and deliver drugs directly to affected areas of the central nervous system (CNS) [12]. These nano-carriers can encapsulate, protect, and control the release of therapeutic agents, thereby increasing bioavailability and reducing systemic toxicity. Importantly, NPs can be functionalized with targeting ligands, such as antibodies or peptides, to enable site-specific delivery. NPs can also be designed to respond to stimuli, such as pH or enzymatic activity, to control drug release. These features make NPs ideal for delivering fragile molecules, such as neurotransmitter precursors, receptor modulators, and gene-editing tools, in cases of biogenic amine deficiency [13].

Several studies have examined the use of liposomes, polymeric nanoparticles, solid lipid nanoparticles, and metallic nanostructures to improve the delivery of dopaminergic, serotonergic, and noradrenergic agents [14,15]. Some preclinical findings suggest that these delivery systems can enhance behavioral and biochemical outcomes in animal models of Parkinson’s disease and depression. However, the long-term safety, immunogenicity, and metabolic fate of various nanomaterials in the brain are still controversial topics [16]. In particular, opinions differ on the neurotoxicity of metallic nanoparticles and the risk of chronic inflammation or accumulation [17]. These concerns underscore the need for balanced evaluations of the therapeutic potential and biological risks of nanotechnological interventions in neurology.

The overarching goal of this work is to support the development of effective and safe next-generation treatments for patients with complex neurochemical imbalances. To this end, we review and synthesize the current knowledge on using nanoparticles to treat brain disorders associated with biogenic amine deficiencies. We also examine the advantages that these pharmaceutical interventions can overcome the limitations of conventional therapies in terms of pharmacokinetics and pharmacodynamics. Additionally, we review preclinical evidence related to efficacy and safety.

1.1. Catecholamines

The catecholamines DA, NE, and epinephrine (EPI), regulate various physiological functions in the nervous, endocrine, and cardiovascular systems. In the CNS, DA influences motor control and motivation, NE controls alertness, attention, and the stress response, and EPI contributes to the sympathetic response to stress, though it primarily acts as a hormone [18].

The synthesis process begins when the enzyme tyrosine hydroxylase (TH) converts tyrosine into 3,4-dihydroxyphenylalanine (DOPA). DOPA then transforms into DA, NE, and finally, EPI. TH is the rate-limiting enzyme (Figure 1), and its human isoforms are distributed differently in regions associated with neuropsychiatric disorders [3,19].

Two enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), break down catecholamines. These enzymes produce metabolites such as dihydroxyphenylglycolaldehyde (DOPGAL), 3,4-dihydroxymandelic acid (DOMA), 3,4-dihydroxyphenylglycol (DOPEG), 3-methoxy-4-hydroxyphenylglycol (MOPEG), and vanillylmandelic acid (VMA) (Figure 2). These processes occur in neurons and peripheral tissues, and alterations to them may contribute to neuropsychiatric and autonomic dysfunction [20,21].

Dopamine originates in two areas of the brain: the substantia nigra and the ventral tegmental area. From there, it projects to the striatum, prefrontal cortex, and limbic system. Norepinephrine is synthesized in the locus coeruleus and projects to various cortical and subcortical structures. Epinephrine is produced in the adrenergic nuclei of the medulla oblongata and plays a role in autonomic control (Figure 3). These neural networks modulate motor, emotional, cognitive, and homeostatic functions [22,23,24].

1.2. Brain Diseases Related to Catecholamine Deficiencies

Major depression is characterized by decreased levels of the neurotransmitters DA and NE in key regions of the brains such as the prefrontal cortex and limbic system (Figure 3). These deficiencies produce symptoms such as anhedonia, apathy, fatigue, sleep disturbances, and cognitive impairment. At the pathophysiological level, dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis and an altered stress response have been identified, accompanied by changes in adrenergic neurotransmission [25,26].

Alzheimer’s disease (AD) is traditionally classified as a neurodegenerative disorder that presents a wide range of neuropsychiatric symptoms, including depression, apathy, anxiety, and behavioral disturbances. The degeneration of the locus coeruleus and the progressive loss of NE partly explain these symptoms (Figure 3). This loss affects cognitive and emotional functions. Additionally, dopaminergic impairment in moderate and advanced stages is associated with demotivation, impaired judgment, and behavioral disturbances. EPI deficiency has also been linked to autonomic dysfunction and stress vulnerability. For these reasons, Alzheimer’s disease is considered a disease with prominent neuropsychiatric components [27,28,29].

Parkinson’s disease is an example of a motor disorder with significant neuropsychiatric origins and manifestations. The loss of dopaminergic neurons in the substantia nigra (Figure 3) causes the classic motor symptoms of the disease, while deterioration of the mesocortical and mesolimbic pathways is associated with depression, anxiety, apathy, sleep disorders, and mild cognitive impairment. Degeneration of the locus coeruleus and decreased NE levels contribute to autonomic dysfunction, fatigue, and attention deficits. Though it is less studied, reduced EPI may also exacerbate dysautonomia symptoms [30,31]. The early and persistent presence of these neuropsychiatric symptoms suggests that Parkinson’s disease is a neurological disorder with significant psychiatric implications.

1.3. Challenges in the Treatment of Neuropsychiatric Diseases: The Blood–Brain Barrier (BBB)

Pharmacological treatment for neuropsychiatric disorders, such as depression, Parkinson’s disease, and Alzheimer’s disease, involves the use of drugs to restore the balance of catecholaminergic neurotransmitters, including DA, NE, and EPI. However, the BBB can limit the efficacy of these therapies by restricting the entry of therapeutic compounds into the central nervous system (CNS). The BBB is formed by endothelial cells joined by tight junctions, as well as by perivascular astrocytes and pericytes [11,32]. This barrier acts as a highly regulated selective filter. Under normal conditions, it prevents the passage of hydrophilic molecules, high-molecular-weight molecules, or substrates of efflux systems, such as P-glycoprotein (P-gp) [33]. The BBB also contains metabolizing enzymes, such as monoamine oxidase (MAO) and cytochrome P450 (CYP450), which degrade compounds before they can enter the brain parenchyma [34]. Nevertheless, this barrier is not static. In neurodegenerative and psychiatric disorders, the BBB undergoes structural and functional alterations that radically modify the drug transport [35].

Recent studies have shown that the BBB exhibits increased paracellular permeability in major depression, which is likely due to neurovascular inflammation and astrocyte dysfunction [36]. This condition may allow certain molecules to enter the brain. However, it can also activate compensatory efflux mechanisms that reduce the brain’s concentration of drugs such as bupropion (Figure 4), a NE and DA reuptake inhibitor. Although bupropion is moderately lipophilic, the presence of a secondary amine and a ketone group in its structure impairs its ability to cross the BBB passively. Bupropion is also a substrate of P-gp, so its concentration in regions such as the prefrontal cortex and limbic system may be insufficient [37]. This is particularly problematic in cases of treatment-resistant depression because low brain penetration results in poor clinical responses, longer therapeutic latency, and the need for increased doses. This increases the risk of systemic adverse effects.

It is well known that the BBB undergoes significant alterations in Parkinson’s disease. The expression of tight junction proteins, such as claudins and occludins [38], decreases. Chronic neuroinflammation has also been documented. These changes can lead to an increase in unwanted molecules entering the brain, which can alter active transport mechanisms, such as L-type amino acid transporter 1 (LAT1). LAT1 is responsible for the entry of L-DOPA [39]. L-DOPA is a hydrophilic molecule that depends entirely on LAT1 to cross the BBB and compete with amino acids in the diet [40] (Figure 4). Alteration of this system, either through saturation or structural damage to the BHE, can lead to unpredictable variability in brain bioavailability. Additionally, enzymes that metabolize L-DOPA, such as COMT and DOPA decarboxylase [41,42], are found in the cerebral endothelium and degrade L-DOPA before it can reach the striatum. This results in clinically significant motor fluctuations, the necessity of complex dosing regimens, and the onset of dyskinesias due to DA spikes associated with intermittent, nonphysiological drug entry.

In the case of Alzheimer’s disease, changes to the BBB are more extensive and have multiple causes. The accumulation of β-amyloid damages endothelial and astrocytic cells directly, reducing BBB integrity [43]. Chronic inflammation, microglial activation, and mitochondrial dysfunction further impair active transport and increase nonspecific permeability [44]. Drugs such as nortriptyline and dopaminergic agonists, which are used to treat behavioral symptoms like apathy and agitation, present unique challenges. Nortriptyline is lipophilic; however, its cerebral action is limited because it is a P-glycoprotein (P-gp) substrate [45] (Figure 4). Neuroinflammation reduces nortriptyline’s effective entry. Drugs such as pramipexole and ropinirole partially cross the BBB, but their therapeutic concentration is affected by active efflux transport and intracerebral metabolism [46,47]. These phenomena result in an unstable pharmacological response, particularly in advanced stages of Alzheimer’s disease, when barrier alterations are more severe and widespread.

1.4. Nanoparticles: New Therapeutic Strategies for Neuropsychiatric Diseases

Recent advances in nanotechnology have enabled the design of nanoparticle-based systems that can cross the BBB and deliver neuroactive drugs directly to the CNS. These systems can be made from lipids, polymers, metals, or proteins. Their size, surface charge, and functionalization can be tailored to optimize pharmacokinetics, enhance stability, and improve interaction with biological barriers. Researchers have leveraged this versatility to encapsulate antidepressants, dopaminergic agonists, catecholamine precursors, and neuroprotective agents for the treatment of Parkinson’s disease, depression, and Alzheimer’s disease. Figure 5 illustrates the preclinical settings in which nanoparticle platforms have been evaluated.

2. Materials and Methods

A comprehensive narrative literature review was conducted to identify and synthesize scientific evidence on the use of nanoparticles to treat brain disorders related to biogenic amine deficiencies. The search was performed across three major electronic databases—PubMed, Web of Science, and Scopus—and covered studies published by July 2025. The following keywords were used: “nanoparticles”, “nanotechnology”, “biogenic amines”, “dopamine”, “norepinephrine”, “depression”, “Parkinson’s disease”, “Alzheimer’s disease”, “drug delivery”, “blood–brain barrier”, “efficacy”, and “toxicology”. Filters were applied to include only original research, preclinical studies, or clinical trials written in English and published as peer-reviewed articles. Articles were included if they addressed the role of biogenic amines in brain function or pathology and discussed the use of nanoparticles (NPs) for drug delivery or therapeutic intervention in the CNS. Studies unrelated to the CNS or biogenic amine pathways and editorials letters were excluded.

Two independent reviewers screened the titles and abstracts of the studies. Then, they performed an analysis to determine their eligibility. Any disagreements were resolved by consensus. Relevant data were extracted from each selected study, including information on the type of nanoparticles used, the targeted neurotransmitter system, the experimental model (in vitro or in vivo), how the BBB was crossed, therapeutic efficacy, and toxicology outcomes.

3. Results and Discussion

The initial screening, based on the aforementioned terms, identified 1200 documents. After applying filters and removing duplicates, the set was reduced to 572 documents. After a manual review to verify the inclusion and exclusion criteria, 53 documents were selected for the review article. The selected studies examined variables such as BBB crossing mechanisms, controlled release profiles, brain bioavailability, neuronal toxicity, and therapeutic effects in models of Parkinson’s disease, depression and Alzheimer’s disease. Parkinson’s disease (PD) was the most researched condition (54.6% of the studies), followed by depression (22.6%) and Alzheimer’s disease (AD) (11.4%). For PD, polymeric NPs were the most commonly used nanotechnology platform for brain targeting strategies (22.6% of cases), followed by lipid-based NPs (11.3%), metallic NPs (7.5) and hybrid NPs (7.5%), and mesoporous NPs (5.6%). For depression, polymeric NPs were the most commonly reported (13.2%) followed by lipid-based NPs (7.5%) and mesoporous NPs (1.9%). Similarly, polymeric NPs were the most common for AD (5.7%), followed by metallic NPs (3.8%) and mesoporous NPs (1.9%). Notably, 11.4% of NPs developed for neuropsychiatric diseases induced toxic effects, all of these corresponded to metallic NPs (Figure 6).

Table 1. Nanoparticle-based strategies for catecholaminergic drug delivery in neuropsychiatric diseases. PLGA, Poly(lactic-co-glycolic acid; PEG, polyethylene glycol; TH, Tyrosine hydroxylase; DA, dopamine; NE, norepinephrine; EPI, Epinephrine; BBB, Blood–brain barrier; BDNF, Brain-derived neurotrophic factor; EGCG, Epigallocatechin gallate; TNF-α, Tumor necrosis factor-alpha; IL-1β, Interleukin-1 beta; SOD, Superoxide dismutase; CAT, catalase; COX-2, Cyclooxygenase-2; L-DOPA, levodopa; GSH, glutathione; 5-HT, serotonin; PK, pharmacokinetic; ROS, reactive oxygen species; AChE, Acetylcholinesterase; P-gp, P-glycoprotein; DAT, Dopamine transporter; PAMAM, polyamidoamine. An up arrow indicates an increase, and a down arrow indicates a decrease.

Nanoparticle Type (NPs)/Size	Material	Drug(s)	Administration Route/Specie	Target Disease(s)	Mechanism/Key Features	Main Therapeutic Outcomes	Ref.
Polymeric/≈150 nm	PLGA	Ropinirole	Intraperitoneal (1 mg/kg/day)/Male rat	Parkinson’s disease	↑ TH in substantia nigra	Reversal of motor symptoms	[48]
Nanoemulsion/≈10 nm	Lecithin/Peanut oil	DA	Oral (25 mg/kg)/Male rat	Parkinson’s disease	Restores DA & NE in hippocampus/striatum, ↓ TNF-α, IL-1β	↓ oxidative stress & neuroinflammation	[49]
Polymeric/≈120 nm	PLGA	DA	Intravenous (4.5 mg/kg)/Rat	Parkinson’s disease	↑ DA in striatum, avoids DA oxidation	Reverses neurochemical & behavioral deficits	[50]
Nanocapsule/≈92 nm	Polymeric core functionalized with Angiopep-2 and cRGD	DA, CAT	Intravenous (600 µg/kg)/Male mouse	Parkinson’s disease	↑ DA in striatum/Substantia nigra, ↑ TH, ↓ α-synuclein	↓ oxidative stress & inflammation	[51]
Polymeric/≈100 nm	Poly(ethylene oxide)/poly(ε-caprolactone) copolymer/GSH	L-DOPA, curcumin	-	Parkinson’s disease	GSH functionalization to cross BBB	Biocompatible with neuroendocrine cells	[52]
Mesoporous NPs/≈100 nm	Tetraethyl orthosilicate	L-DOPA	-	Parkinson’s disease	Sustained release at pH 7.4, minimal gastric release	pH-dependent release	[53]
Mesoporous NPs/≈200 nm	Na+ cation–π	L-DOPA	-	Parkinson’s disease	Sustained release, ↓ α-synuclein aggregation	High neuronal biocompatibility	[54]
Metallic/≈20 nm	Zinc oxide	L-DOPA	Oral (30–60 mg/kg)/Male rat	Parkinson’s disease	Protects neurons in the substantia nigra, ↓ α-synuclein	improved motor function	[55]
Solid Lipid NPs/≈260 nm	Glycerol tripalmitin, polysorbate 80, chitosan	DA	-	Parkinson’s disease	Nanocarrier for DA	Efficient BBB transit in vitro	[56]
Solid Lipid NPs/≈150 nm	Gelucire®, Tween 85, Glycol Chitosan	DA	-	Parkinson’s disease	Sustained release of DA	Potential intranasal route	[57]
Polymeric/≈350 nm	PLGA	DA, Albumin	Intraperitoneal (10 and 20 mg)/Male mouse	Parkinson’s disease	↑ DA in striatum and substantia nigra	↑ Motor coordination	[58]
Polymeric/≈300–500 nm	Chitosan, sodium tripolyphosphate	Pramipexole	Intranasal (0.3 mg/kg)/Male rat	Parkinson’s disease	↑ DA, SOD, and CAT	↓ catalepsy	[59]
Hollow mesoporous NPs/≈550 nm	Chitosan, alginate	Pramipexole	SH-SY5Y cells (200 µg/mL)	Parkinson’s disease	↓ Oxidative stress	Neuroprotection	[60]
Liposome/≈120 nm	PEG, Dipalmitoylphosphatidylcholine	Pramipexole	Intraperitoneal (0.5 mg/mL)/Male rat	Parkinson’s disease	↑ DAT	↓ Dose	[61]
Niosome/≈100 nm	PEG, polyglyceryl-3 cetyl ether	Pramipexole	Intraperitoneal (0.5 mg/mL)/Male rat	Parkinson’s disease	↓ DAT	↓ Dose
Polymeric/≈50 nm	Tannic acid, polyvinyl alcohol	L-DOPA	Subcutaneous (2 mg)/Rat	Parkinson’s disease	↓ ROS, ↑ DA, TH, and SOD in striatum	↓ Movement disorders and cerebral oxidative stress	[62]
Metallic/≈200 nm	Chloroauric acid, cholesterol, lecithin	α-synuclein DNA plasmid, docosahexaenoic acid, nerve growth factor	Intraperitoneal (2 mg/kg)/Male mouse	Parkinson’s disease	↓ α-synuclein, ↑ TH in substantia nigra	↑ Spatial memory ↓ motor dysfunction	[63]
Dendrimer	PAMAM, PEG	Lactoferrin vector	Intravenous/Male rat	Parkinson’s disease	↑ TH in substantia nigra, ↑ DA in striatum	↑ Locomotor activity	[64]
Porous polysaccharides/≈100 nm	Maltodextrin, lipid core	TH	Intracranial (3 µL)/Male mouse	Parkinson’s disease	↑ TH in caudate putamen	↑ TH activity	[65]
Hybrid (Metallic/Polymeric)/≈110 nm	Copper oxide, polyvinylpyrrolidone	Pramipexole	Drosophila melanogaster (46.5 µg via diet)	Parkinson’s disease	↑ DA, AChE and GSH	↓ locomotor defects	[66]
Solid Lipid NPs/≈150 nm	Stearyl alcohol, poloxamer 188, Tween 80	Duloxetine	Intraperitoneal (30 mg/kg)/Male rat	Depression	80% encapsulation, 52% sustained release	↑ BDNF, ↓ TNF-α, COX-2 in prefrontal cortex	[67]
Solid Lipid NPs/≈300 nm	Glyceryl monostearate, Tween 80, Span 80	Venlafaxine	Oral (22 mg/kg)/Male mouse	Depression	Surfactants ↑ BBB penetration	↑ Brain bioavailability	[68]
Polymeric/≈120 nm	PLGA, chitosan	Duloxetine	Intranasal (20 mg/kg)/Male rat	Depression	↑ NE in brain via trigeminal/olfactory transport	↑ Antidepressant activity	[69]
Polymeric/≈170 nm	PLGA, chitosan	Desvenlafaxine	Intranasal (5 mg/kg)/Male rat	Depression	↑ NE in brain	Reversed the signs of depression in rats	[70]
Polymeric/≈200 nm	PLGA	Venlafaxine	Intranasal (10 µL/day)/Male mouse	Depression	Direct brain transport, rapid onset	Reversed anhedonia, reduced immobility in 7 days	[71]
Polymeric/≈50 nm	PLGA, dextran	Fluoxetine	Oral (30 mg/kg/day)/Rat	Depression	↑ 5-HT & DA, improved PK	↑ Antidepressant activity	[72]
Mesoporous NPs	Tetraethyl orthosilicate	Duloxetine	-	Depression	pH-dependent release	Controlled release in intestinal pH	[73]
Solid Lipid NPs/≈190 nm	Poloxamer 188	Venlafaxine	Intravenous (11 mg/kg)/Male mouse	Depression	↓ P-gp activity	↑ Brain concentration	[74]
Polymeric/≈200 nm	copolymer `poly (methyl vinil ether/Maleic acid)	Amitriptyline	Intranasal (10 mg/kg)/Male and female rat	Depression	↑ BBB penetration	↑ Antidepressant activity	[75]
Bilosome/Niosome/≈250–350 nm	Bile salt, span 20, cholesterol	Bupropion	Zebrafish	Depression	↑ Encapsulation	↓ Depressive behavior	[76,77]
Polymeric/≈140 nm	Polysorbate 20, poloxamer 420, polycaprolactone	L-tyrosine	Intraperitoneal (5–10 mg/kg)/Male rat	Depression	↑ NE	↑ Locomotor activity ↓ Depressive behavior	[78]
Metallic	Chloroauric acid	Polydopamine	-	Alzheimer’ s disease	↓ β-amyloid aggregation and cytotoxicity.	Neuroprotector	[79]
Nanocomposite/≈25 nm	-	DA, tryptophan, EGCG, BDNF	-	Alzheimer’ s disease	↓ β-amyloid fibrillation, ↓ neuronal damage, ↓ brain inflammation	↑ Cognitive function	[80]
Polymeric/≈170–240 nm	PLGA, PEG	Donepezil	Intravenous (15 µg/kg)/Male rat	Alzheimer’ s disease	↓ AChE activity, ↓ fibril formation, ↓ inflammatory markers	↑ Memory	[81,82]
Mesoporous NPs/≈120 nm	Tetraethyl orthosilicate	DA, GSH	-	Alzheimer’ s disease	↓ ROS	Neuroprotection	[83]
Polymeric/≈100 nm	NaOH	Polydopamine	Caenorhabditis elegans (100 µg/mL)	Alzheimer’ s disease	↓ fibril formation, ↓ ROS	↓ deposition of β-amyloid plaque	[84]
Magnetic/≈600 nm	Iron chloride, PEG, 3-aminopropyl-trimethoxysilane	TH	-	Therapeutic potential for treating diseases caused by catecholamine deficiencies.	↑ L-DOPA synthesis in vitro	-	[85]
Metallic/≈45 nm	Iron oxide	-	Oral (25–50 µg/kg)/Male mouse	Safety studies	↓ DA & EPI in prefrontal cortex and cerebellum, ↑ NE in hippocampus	↓ Motor coordination and memory	[86]
Metallic/≈10 nm	Titanium dioxide	-	Oral (10–50 mg/kg)/Male mouse	Safety studies	↓ TH in substantia nigra	Parkinson’s-like symptoms	[87]
Metallic/≈10 nm	Iron oxide	-	Intravenous (50 mg/kg)/Male rat	Safety studies	↓ DA in striatum, ↑ ROS, ↑ α-synuclein	Neurotoxicity	[88]
Metallic/≈30–60 nm	Manganese dioxide	-	Intraperitoneal (50–100 µg/kg)/Male rat	Safety studies	↓ DA & NE in hippocampus, ROS production, lipid peroxidation	Depression-like behaviors	[89]

summarizes representative nanoparticle systems and their key characteristics. Notably, none of these systems have advanced to human clinical trials for catecholaminergic drugs. This underscores the preclinical nature of the reviewed evidence and the existing translational gap.

3.1. Influence of Particle Size on Catecholaminergic Restoration

The size of nanoparticles significantly impacts their efficacy and safety. An optimal performance range of 90–200 nm is commonly observed, particularly in polymeric and lipid systems. These systems can cross the BBB, restore dopamine and norepinephrine levels in regions such as the striatum and hippocampus, and exhibit low toxicity. For example, dopamine-loaded poly(lactic-co-glycolic acid) (PLGA) NPs (approximately 120 nm) prevent neurotransmitter oxidation and reverse neurochemical and behavioral deficits in Parkinson’s disease models [50]. Additionally, Angiopep-2- and cRGD-functionalized nanocapsules (approximately 92 nm) increase dopamine levels and tyrosine hydroxylase expression in the substantia nigra, thereby reducing α-synuclein aggregates [51]. Lipid nanoparticles in this size range (150–190 nm) containing venlafaxine or duloxetine demonstrate improved brain bioavailability through efflux transporter modulation and sustained release [67,68,74].

An experimental study in mice revealed that focused ultrasound combined with microbubbles achieved the highest efficiency in delivering intermediate-sized gold nanoparticles (≈15 nm) to the brain compared to smaller or larger NPs. The optimal size for metallic NPs is explained by a balance between permeability through the BBB and systemic elimination [90].

3.2. Polymeric Nanoparticles

Some of the most extensively studied NPs are made of PLGA. These NPs are biocompatible and biodegradable and they can encapsulate both hydrophilic and lipophilic drugs. Ropinirole formulated in PLGA NPs achieved an encapsulation efficiency of 74%, sustained release over five days, and caused reversal of motor symptoms in rotenone-treated rats [48]. In Parkinson’s disease, L-DOPA PLGA NPs prevent COMT degradation, thereby increasing effective drug delivery [91]. In a reserpine-induced model, DA or L-DOPA NPs restored DA and NE levels in the hippocampus and striatum. The NPs also reduced proinflammatory cytokines and remained stable for 90 days at room temperature [49]. Similarly, when administered intravenously to 6-hydroxydopamine (6-OHDA)-lesioned rats, PLGA NPs loaded with DA crossed the BBB and released 60% of DA over seven days. This reversed neurochemical and behavioral deficits, prevented DA oxidation, and avoided cardiovascular toxicity [50]. Chitosan-coated PLGA NPs enhanced mucosal adhesion and BBB transport in duloxetine- and desvenlafaxine-based systems, achieving higher NE levels and improved antidepressant activity [69,70].

Polymeric NPs are optimal for the sustained release and protection of labile catecholaminergic drugs from enzymatic degradation. Their ability to encapsulate small molecules, such as L-DOPA and duloxetine, as well as biomolecules, such as enzymes, expands therapeutic possibilities. However, variability in encapsulation efficiency and potential burst release in vivo remain challenges. Optimizing polymer ratios and surface modifications may improve controlled release and reduce systemic peaks that trigger side effects. Additionally, polymeric nanoparticles that are sensitive to reactive oxygen species (ROS) have been developed. These nanoparticles based on poly(2,2′-thiodiethylene-3,3′-thiodipropionate) (PTT) respond to an oxidative environment following an ischemic event. Then, they release their therapeutic payload into the injured brain tissue. These systems have demonstrated effective neuroprotection in animal stroke models [92].

3.3. Lipid Nanoparticles

Solid lipid nanoparticles (SLNPs) and nanostructured lipid carriers (NLCs) effectively stabilize lipophilic drugs such as duloxetine and allow for greater drug loading. Venlafaxine encapsulated in SLNPs improves bioavailability and brain penetration when administered intravenously, aided by biocompatible surfactants that prolong plasma circulation and facilitate transcellular passage across the BBB [67,68,74]. Duloxetine encapsulated in SLNPs composed of stearyl alcohol and the surfactants poloxamer 188 and Tween 80 achieved 80% encapsulation efficiency and 52% sustained release following intraperitoneal administration [67]. Venlafaxine-loaded SLNPs improve BBB penetration by modulating P-gp activity [74]. DA-loaded chitosan-coated SLNPs exhibited high in vitro BBB transit and are suitable for intranasal delivery [56,57].

Lipid-based systems are particularly advantageous for highly lipophilic drugs that are unstable in plasma. These systems allow for passive diffusion across the BBB and active uptake via surfactant-mediated modulation of efflux transporters. However, they tend to undergo polymorphic transitions during storage, which can compromise drug retention. Hybrid lipid-polymer matrices could provide stability and a high loading capacity. A combination of gold nanoparticles and exosomes has been shown to effectively cross the BBB and bind selectively to neuronal cells [93]. This approach shows promise for targeting treatments for neurological disorders.

3.4. Levodopa and Dopaminergic Formulations

Innovative systems have been developed to optimize the use of levodopa and other dopaminergic drugs. In a mouse model of Parkinson’s disease, dopamine- and catalase-loaded nanoparticles (NPs) modified with Angiopep-2 peptide (which binds to the low-density lipoprotein receptor-related protein 1) and cyclic arginine-glycine-aspartic acid (cRGD) (which targets integrin receptors) crossed the BBB. These NPs increased DA levels by 1.8- and 3.5-fold in the striatum and substantia nigra, respectively. The NPs also improved neuronal markers, such as tyrosine hydroxylase, the dopamine transporter, and the dopamine D₂ receptor [51]. Despite their low encapsulation efficiency (3.6%) biodegradable poly(ethylene oxide)/poly(ε-caprolactone) copolymer NPs functionalized with glutathione and loaded with L-DOPA and curcumin, successfully crossed the BBB [52]. L-DOPA modified with fatty acids and loaded into mesoporous silica nanoparticles enabled sustained release at pH 7.4 and minimal release under gastric conditions [53]. Mesoporous NPs based on Na⁺-mediated cation-π interactions (L-DOPA-DA-MNPs) inhibited α-synuclein aggregation and achieved sustained drug release. These nanoformulations showed high neuronal biocompatibility [54]. Zinc oxide nanoparticles (21 nm) modified with L-DOPA reduced α-synuclein aggregates and improved motor function in rats. These nanoparticles exhibited synergistic antioxidant effects; however, higher doses decreased efficacy [55,94].

NPs systems address a key limitation of L-DOPA therapy: fluctuating brain levels. They provide sustained release and neuroprotective co-delivery. Mesoporous carriers offer precise, pH-dependent release, which minimizes peripheral conversion. However, long-term toxicity studies are required for metal-based systems (e.g., zinc oxide nanoparticles), due to the potential for accumulation and oxidative reactivity.

3.5. Blood–Brain Barrier Transport Mechanisms

Receptor-mediated transcytosis (RMT) is one of the most efficient strategies for crossing the BBB. It uses ligands that bind to receptors, such as transferrin, insulin, LDLR, and lactoferrin. Examples include PLGA NPs for venlafaxine [71] and chitosan-coated SLNPs for DA [56], which improve permeability, especially when glycol chitosan is added to enhance encapsulation and stability [57]. Adsorptive-mediated transcytosis (AMT) is based on electrostatic interactions and can be enhanced with cationic coatings such as chitosan or polyethyleneimine coatings. AMT is useful in advanced disease stages when RMT receptor availability is reduced, though excessive surface charge may cause toxicity [95,96,97]. Another approach involves opening the BBB temporarily via focused ultrasound with microbubbles. This method has enabled the targeted delivery of curcumin- or growth factor-loaded liposomes in Parkinson’s disease and Alzheimer’s disease models. It improves dopaminergic function without causing adverse effects [98,99,100].

RMT offers high selectivity, but its effectiveness depends on receptor expression, which decreases with advanced neurodegeneration. AMT is an alternative, but it carries a higher risk of toxicity due to non-specific uptake. Physical modulation of the blood–brain barrier (BBB) using ultrasound can complement these strategies, but precise dosing is required to avoid microvascular damage.

3.6. Intranasal Administration

The intranasal route bypasses hepatic metabolism and the BBB, utilizing trigeminal and olfactory pathways. PLGA NPs loaded with duloxetine or desvenlafaxine and coated with chitosan have demonstrated increased permeability, higher brain bioavailability, and elevated noradrenaline levels and improved antidepressant activity [69,70]. Intranasally administered venlafaxine-loaded PLGA NPs reversed anhedonia and reduced immobility within seven days in mice with corticosteroid-induced depression, even at doses at which the free drug was ineffective [71].

Intranasal delivery is a noninvasive alternative that allows for rapid penetration of the CNS, making it ideal for managing acute symptoms. However, mucociliary clearance and variable absorption rates are limitations. Mucoadhesive polymers (e.g., chitosan) can improve residence time, but they may cause nasal irritation with chronic use.

3.7. Controlled-Released and Smart Systems

Nanotechnology enables the development of sustained-release and targeted delivery systems, which reduce plasma fluctuations and adverse effects. For instance, fluoxetine nanoparticles conjugated with dextran demonstrate pH-sensitive release and improved oral pharmacokinetics [72]. Duloxetine formulated in mesoporous silica nanoparticles exhibits pH-dependent release, maintaining high concentrations in acidic environments while nearly completing its release at intestinal pH levels [73].

These pH-activated systems allow for localized action in neuroinflamed brain regions. Combining these systems with antioxidants such as resveratrol or curcumin improves synaptic plasticity and catecholaminergic neurotransmission in Alzheimer’s disease models exhibiting depressive symptoms. In Parkinson’s disease models, a combination of L-DOPA and amantadine PLGA-NPs achieved 50-h sustained release and reduced dyskinesias [101]. Meanwhile, pramipexole in thermosensitive gels, which remain stable for 90 days, reduced the treatment burden [102].

Smart release systems can synchronize drug delivery with pathological conditions such as acidic pH levels and oxidative stress. This reduces systemic exposure and improves efficacy. However, the complexity of the formulation may hinder scalability and regulatory approval. Furthermore, ensuring that the triggering stimulus is disease-specific remains challenging.

3.8. Hybrid and Multifunctional Systems

The use of hybrid NPs is an advanced therapeutic approach that integrates polymeric, lipidic, metallic, and biological components into unified platforms. This allows for the development of combination therapies that target multiple pathological mechanisms simultaneously. For instance, copper oxide-pramipexole hybrids coated with polyvinylpyrrolidone (PVP) have been shown to significantly improve locomotor function in a Drosophila model of Parkinson’s disease. These hybrids increase DA, glutathione (GSH), and acetylcholinesterase (AChE) levels, exhibiting dual antioxidant and dopaminergic activity [66]. Similarly, gold NP composites functionalized with neurotrophic factors (docosahexaenoic acid and nerve growth factor) reduced α-synuclein aggregation and improved spatial memory in murine models [63]. Dendrimer-based systems, such as poly(amidoamine)-polyethylene glycol-lactoferrin conjugates, facilitate targeted gene delivery to restore tyrosine hydroxylase (TH) expression in dopaminergic regions [64]. Porous maltodextrin NPs, meanwhile, enable the efficient delivery of enzymes (e.g., TH) to counteract catecholamine deficiencies.

The intricate synthesis parameters of hybrid systems, such as phase segregation in core–shell structures, make them difficult to fabricate. Additionally, metallic components, such as copper and gold, may catalyze oxidative reactions or alter drug release kinetics. The difficulty of standardizing physicochemical characterization increases regulatory hurdles. Using noble metals (e.g., gold) or targeting ligands (e.g., lactoferrin) increases production costs. Furthermore, the long-term biodegradability of metal-polymer hybrids is uncertain. Incomplete degradation could result in chronic neurotoxicity or bioaccumulation.

3.9. Genetic Modulation of Therapeutic Targets

Nanoparticle-mediated gene delivery has emerged as a transformative strategy for precisely targeting catecholaminergic dysfunction in neuropsychiatric disorders. This strategy leverages nanocarriers to restore enzymatic pathways, deliver neurotrophic factors, or silence pathological genes. As shown in Table 1, lactoferrin-modified nanoparticles allow for receptor-mediated transcytosis across the BBB. This enables the delivery of therapeutic genes to the substantia nigra in Parkinson’s disease models. This enhances TH expression and dopamine synthesis [64]. Similarly, magnetic nanoparticles immobilized with human TH exhibited efficient enzymatic activity in vitro, positioning them as potential tools for enzyme replacement therapy in catecholamine-deficient conditions [85]. Another complementary approach used gold nanoparticle-DNA plasmid complexes to suppress α-synuclein aggregation. This approach improved motor coordination and spatial memory in murine models through targeted gene silencing [63].

Although nanocarriers overcome key limitations of viral vectors, such as reduced immunogenicity and tunable release kinetics, neuronal transfection remains suboptimal due to nuclear membrane barriers. These barriers often necessitate high nanoparticle doses, increasing off-target risks. These off-target effects could disrupt non-catecholaminergic circuits. Additionally, the long-term epigenetic consequences of sustained gene modulation remain unclear.

3.10. Safety Considerations

The physicochemical properties of NPs, such as size, shape, surface charge, and reactivity influence their interactions with neuronal and glial cells, as well as the immune system. Key risks include cytotoxicity and oxidative stress. For example, silver nanoparticles (AgNPs) can block lysosomal fusion and activate microglia [103], and manganese dioxide nanoparticles (MnO₂ NPs) can induce depression-like behavior and reduce hippocampal catecholamines [89]. Bioaccumulation is another concern. This phenomenon has been observed with metallic nanoclusters [104] and duloxetine-loaded PLGA NPs, which show prolonged brain retention [105].

Metallic NPs offer unique functionalities, such as magnetic guidance and catalytic activity. However, concerns have been raised about their long-term safety profile. These systems reduce tyrosine hydroxylase in the substantia nigra and decrease dopamine and norepinephrine in the hippocampus and prefrontal cortex. They also generate Parkinson’s- or depression-like phenotypes. These effects are due to the systems’ high surface reactivity and their ability to induce oxidative stress and glial inflammation [86,87,88,89]. Preclinical evaluations must address the effects of chronic exposure, bioaccumulation, and immune activation beyond short-term efficacy before clinical application.

3.11. Clinical Translation of Catecholamine-Based Nanoparticles

Currently, there are no clinical studies on using catecholamine-based nanoparticles to treat diseases such as PD, AD, and depression. In fact, the National Library of Medicine only has records of two nanoparticle-based studies on these conditions. One study was a phase two trial that examined the redox state of patients’ brains diagnosed with PD after they ingested CNM-Au8, gold nanocrystals with a particle size below 20 nm, orally at doses ranging from 7.5 to 60 mg daily for 12 weeks [106,107]. The second study evaluated APH-1105, an α-secretase modulator formulated as intranasal nanoparticles, as a treatment for mild to moderate cognitive impairment in patients with AD. It was administered at doses of 0.5–2 µg twice weekly for 12 weeks [108].

Nevertheless, polymeric and lipid nanoparticles ranging from 90 to 200 nm are closer to being used in clinical applications. This is primarily because materials such as PLGA and lipid excipients have already been approved by regulatory agencies for use in pharmaceutical formulations [109,110]. Although the Food and Drug Administration (FDA) recognizes chitosan as safe [111], it has not yet approved its use in drug delivery systems. However, transitioning from the preclinical stage to clinical practice requires overcoming several limitations. First, physicochemical and biological characterization methodologies must be standardized to ensure reproducibility in parameters such as chemical composition, shape, morphology, particle size, impurities, and chemical, physical and colloidal stability. Other parameters include structural attributes, coating properties, porosity, brain biodistribution, and release and degradation rates. Additionally, the immune response induced by these nanomedicines must be analyzed. Importantly, the environmental impact must also be addressed. Second, integrative translational trials must be designed to evaluate the efficacy of restoring dopaminergic or noradrenergic function, chronic safety, risks associated with specific routes of administration, synaptic plasticity, possible interactions with other neurotransmitter systems, and NP type harmonization. Third, current guidelines for approving nanomedicines for the central nervous system lack specific criteria for neurotransmitter-based therapies. Therefore, regulatory frameworks must be adapted [112,113].

3.12. Future Directions and Challenges

Significant advances have been made over the past two decades in developing nanoparticles as therapeutic vehicles for neuropsychiatric diseases. This technology has overcome critical barriers in neurological pharmacotherapy. However, despite its transformative potential, neuropsychiatric nanomedicine is still in the early stages of development. While most successful studies on the application of nanoparticles in neuropsychiatry have yielded promising results in animal models, including reducing symptoms, improving brain penetration, and decreasing side effects, little progress has been made in applying these findings to humans. This is partly due to the technical difficulty of scaling up the production of nanoparticles with precise physical and chemical properties. To bridge this gap, clinical research platforms must be created that integrate materials engineers, neuroscientists, pharmacologists, and clinicians from the beginning. These platforms should develop protocols that consider radically modify drug transport the multifunctional and dynamic nature of nanoparticles, as well as methods that consider the long-term impacts on the brain, immune processes, and elimination systems, rather than just immediate clinical outcomes.

Neuropsychiatric diseases, such as treatment-resistant depression, Alzheimer’s disease, and Parkinson’s disease, are dynamic and heterogeneous processes that do not follow fixed clinical patterns. Symptoms often do not directly correlate with circulating neurotransmitter levels but rather with functionally altered brain circuits, localized neuroinflammation, synaptic changes, or progressive neurodegeneration. Therefore, future nanotechnological systems must not only release drugs in a sustained manner and act adaptively, intelligently, and specifically according to the patient’s brain state in real time. Nanoparticles that release their contents only in response to pathophysiological signals, such as altered brain pH, elevated oxidative stress, or pathological enzyme activity, are already being developed. However, these technologies must evolve into systems that can interact with neurochemical sensors or functional brain recordings to advance toward true neurological precision medicine.

As nanoparticles become more sophisticated and capable of crossing the BBB, releasing multiple drugs, targeting specific regions, and acting as gene vectors or epigenetic editors, the risks of bioaccumulation, long-term toxicity, and interference with non-target physiological systems increase. Therefore, critical future directions will be to ensure that any nanoparticle entering the brain (1) can be safely degraded or eliminated, (2) does not permanently alter brain homeostasis, and (3) can be tracked as it distributes and functions. This implies the need to develop completely biodegradable materials, temporary self-deactivation mechanisms, and real-time traceability systems using neuroimaging techniques or molecular markers. Nanoparticles entering the brain must behave like “respectful guests,” fulfilling their function without leaving a trace or interfering with basal neurophysiology.

4. Conclusions

Nanoparticle-based drug delivery is a transformative strategy that overcomes the limitations of conventional catecholaminergic therapies for neuropsychiatric disorders. Nanoplatforms, including polymeric, lipid, and hybrid systems, enhance BBB penetration, stabilize labile drugs, and enable targeted release to specific brain regions. These advances significantly improve the efficacy of agents such as levodopa, bupropion, and duloxetine while reducing systemic side effects. These advances offer renewed hope for treating Parkinson’s disease, depression, and Alzheimer’s disease, which are often difficult to treat with traditional pharmacotherapy due to poor bioavailability or off-target toxicity. However, the clinical translation of nanomedicine depends on overcoming critical challenges, such as long-term safety uncertainties, bioaccumulation risks (especially for metallic nanoparticles), and potential disruptions to neurochemical homeostasis. Future success requires a balanced approach that includes developing biodegradable, “smart” carriers that respond dynamically to disease-specific stimuli, creating rigorous preclinical models that address chronic exposure, and establishing adaptable regulatory pathways for nanoscale therapeutics. Interdisciplinary collaboration spanning nanotechnology, neuroscience, and clinical medicine is essential to fully harness this potential. With careful optimization, nanoparticles could usher in a new era of precision neuropharmacology and transform our approach to restoring catecholaminergic balance in the brain.