Nano–Micronutrients of Iron and Copper for Improved Human Nutrition: A Narrative Review

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Nano-formulations of iron and copper as micronutrients hold transformative potential to alleviate micronutrient deficiencies and improve human nutrition, provided technical and regulatory challenges are adequately addressed.

Abstract

Micronutrient deficiencies of iron and copper are global challenges that significantly undermine public health, particularly among vulnerable populations. Recent advancements in nanotechnology have paved the way for nano–micronutrient formulations that offer improved nutrient delivery over conventional supplements. Nano–micronutrients leverage sub-100 nm particle sizes, increased-surface area, and controlled-release mechanisms to enhance gastrointestinal absorption and bioavailability of iron and copper. This narrative review takes a nuanced approach to critically evaluate published literature comparing nano-formulations with traditional supplements, demonstrating that nano–micronutrients enable targeted cellular uptake, reduce interactions with anti-nutritional factors, and improve organoleptic properties of fortified foods. Evidence indicates that these formulations can markedly elevate clinical biomarkers such as serum ferritin and hemoglobin, while reducing required dosages and mitigating gastrointestinal side effects. However, challenges persist regarding long-term safety, production scalability, and regulatory oversight. Public acceptance remains contingent on transparent safety assessments and effective communication of benefits. Future research should focus on standardizing synthesis methods, developing green production processes, and integrating robust in vitro and in vivo models to elucidate long-term health impacts. Overall, nano–micronutrients of iron and copper hold transformative potential to alleviate micronutrient deficiencies and improve human nutrition, provided technical and regulatory challenges are adequately addressed.

1. Introduction

Micronutrient deficiencies, particularly of iron (Fe) and copper (Cu), remain pervasive public health problems globally, notably affecting vulnerable populations such as children and pregnant women [1,2,3]. Iron deficiency is estimated to impact 50% of pregnant women and is the leading nutritional disorder in neonates [4,5]. Further, Fe deficiency is the world’s most common nutritional disorder, significantly contributing to anemia and impaired cognitive and immune functions [1,2]. Copper, although required in trace amounts, is essential for cellular enzymatic redox processes, antioxidant defense, and proper neurological function [6,7]. Traditional micronutrient fortification methods, which use water-soluble salts or conventional chelated compounds, have led to foods with suboptimal bioavailability, organoleptic changes, and variable absorption rates [8,9]. Consequently, researchers have increasingly focused on nano–micronutrients as a promising alternative to enhance nutrient stability, solubility, and cellular uptake [10,11].

Nanotechnology offers unique advantages in nutrient delivery because of particles’ ultrafine size (typically 1–100 nm) and high surface-to-volume ratio, which facilitate dissolution and improved gastrointestinal absorption [11,12,13]. Furthermore, nano-formulations can be designed to release nutrients in a controlled manner, protecting them from degradation under the harsh acidic conditions of the stomach and thereby ensuring enhanced bioavailability in the small intestine [10,14]. Recent investigations into Fe nano-formulations, such as self-assembled Fe-whey protein isolate fibrils and sucrosomial Fe, have demonstrated superior absorption compared to conventional ferrous sulfate due to greater protection from oxidation and increased surface area [11,15]. Similarly, the development of Cu-based nanocarriers offers the potential to achieve more precise dosing while minimizing adverse reactions related to oxidative stress [6,16].

In addition to physical advantages, nano–micronutrients can be engineered through surface modifications or encapsulation in biocompatible matrices to target specific sites of absorption, thereby reducing interactions with anti-nutritional factors such as phytates that inhibit mineral uptake [17,18]. Such targeted approaches are particularly important in plant-based diets where inhibitors of Fe absorption—like the phytates and polyphenols–are more common [1,19,20]. Additionally, traditional supplements’ low absorption rates can lead to Fe and Cu deficiency, highlighting the need for nano-micronutrients’ engineering specificity [21,22,23]. Moreover, emerging evidence from in vivo studies suggests that these nano–micronutrient formulations can improve the bioefficacy of fortified foods without adversely affecting the taste and/or color of food products [8,24,25].

This narrative review, an interpretive form of knowledge synthesis, draws together insights and analyses from published research pertaining to nano–micronutrients of Fe and Cu within the context of improving human nutritional quality, with a goal to succinctly summarize current knowledge and develop new insights, interpretations, and meaningful conclusions on the topic. This narrative review argues that a shift toward nano-enabled delivery systems for Fe and Cu represents a transformative step in combating micronutrient deficiencies among vulnerable populations such as children and pregnant women. By comparing mechanisms, benefits, and challenges across multiple studies, this study underscores the potential of these innovative strategies to enhance human nutrition and public health [10,12,26].

Accordingly, a narrative review of the peer-reviewed literature was conducted using databases such as PubMed, Web of Science, and Google Scholar. Using the Boolean logic method, relevant articles were retrieved for inclusion in this review using the keywords: “nano AND micronutrients”, “nanonutrients AND micronutrients”, “micronutrients AND human health”, “nanonutrients AND human health”, “nanonutrients AND human toxicity”, “nano-copper AND human health”, “nano-iron AND human health”, “nano-copper AND human toxicity”, “nano-iron AND human toxicity”, “nano-copper AND absorption”, “nano-iron AND absorption”, “nanonutrients AND challenges”, and/or “nanonutrients AND regulations”. A total of 984 articles were retrieved, title-reviewed, and 212 articles were retained for abstract review. Upon review of abstracts, 130 articles were included to synthesize information for this narrative review. In the sections that follow, we discuss in detail the mechanisms underlying nano-nutrient delivery and absorption, the myriad benefits observed in preclinical and clinical studies, the challenges and limitations of current formulations, the broader implications for public health, and the outlook for this rapidly evolving area of nano–micronutrient research.

2. Mechanisms of Nano–Micronutrient Delivery

Nano–micronutrients employ several advanced mechanisms that distinguish them from conventional nutrient supplements. The nanoscale size of particles, often less than 100 nm, significantly increases their surface area, which enhances dissolution rates and facilitates absorption across the intestinal epithelium [10,12]. For Fe and Cu, which in their ionic forms often precipitate at physiological pH or form insoluble complexes with dietary inhibitors, the nano-formulations can protect these ions and maintain them in a bioavailable state [8,13]. For example, self-assembled Fe-whey protein isolate fibrils create a compact nanocomposite that ensures Fe remains soluble and less prone to oxidation, thereby facilitating its transport across the intestinal mucosa [15,27].

Moreover, surface modification techniques—such as encapsulation within pH-responsive alginate microcapsules—permit the targeted release of micronutrients in the small intestine [13]. These microcapsules are engineered to resist the acidic environment of the stomach and to disintegrate in the more neutral pH of the intestines, effectively releasing the encapsulated Fe or Cu where absorption is maximized [10,12]. Such controlled-release systems substantially reduce the likelihood of premature degradation or interaction with anti-nutritional compounds, a problem often encountered with unprotected mineral salts [17,18].

Another crucial mechanism is the ability of nano–micronutrients to bypass conventional uptake limitations by utilizing endocytic pathways [28,29]. Studies have shown that nanoparticles can enter intestinal cells via clathrin-mediated endocytosis or macropinocytosis, thereby delivering minerals directly into the cytoplasm where they can be efficiently incorporated into metabolic pathways [11,16]. This enhanced cellular uptake is supported by research indicating that nano-sized delivery systems produce higher blood serum levels of Fe and Cu compared to conventional formulations [11,16].

Currently, only ~2–28% of the Fe in traditional FeSO₄ supplements, and ~58–68% of the Cu in Cu amino acid chelate supplements, are bioavailable in humans [30,31]. Nano–micronutrients can be designed to interact favorably with proteins, such as transferrin for Fe and ceruloplasmin for Cu, which are responsible for systemic distribution of minerals [6,10]. In this context, nano-formulations act as “bio-mimetic” carriers that integrate seamlessly with endogenous mineral transport systems, reducing potential side effects and toxicity [7,8]. These interactions, therefore, mimic the physiological state, facilitating more natural absorption, assimilation, and utilization of the nutrients.

Furthermore, the co-delivery of synergistic compounds, such as vitamin C for Fe, is facilitated by nano-formulations. Vitamin C is known to reduce ferric iron to the more soluble ferrous form; when encapsulated together with nano-Fe, it further enhances Fe absorption by maintaining the optimal redox state [20,32]. Similar strategies have been proposed for Cu, wherein nano-carriers may be co-formulated with antioxidants to mitigate potential oxidative damage [6]. Overall, the advanced mechanistic strategies built into nano–micronutrient formulations represent a significant technological leap over traditional mineral supplements, enabling a more efficient and reliable method for combating micronutrient malnutrition [10].

Mechanistic Insights into Iron and Copper Absorption

Copper absorption through diet necessitates the involvement of specific transport proteins, notably the divalent metal transporter 1 (DMT1) and the high-affinity copper transporter 1 (Ctr1) [33,34]. Upon entry through the diet, Cu primarily exists in its divalent form (Cu²⁺) within the gastrointestinal tract, from which it can be absorbed by intestinal epithelial cells (enterocytes). This uptake occurs through two primary pathways: the nonspecific DMT1, which also facilitates Fe transport, and the specialized Ctr1 for Cu⁺ uptake [35,36,37]. The transport of Cu into enterocytes is largely facilitated by Ctr1, which is assisted by circulating proteins such as ceruloplasmin and transcuprein [33,37]. A schematic depicting the absorption of Cu by enterocytes is presented in Figure 1.

Before Cu²⁺ can be effectively taken up by Ctr1, a biochemical reduction process occurs in which biological vitamin C, acting as a reductant, helps convert Cu²⁺ to Cu⁺ [38]. The resulting intracellular Cu is sequestered in the cytosol, bound by the intracellular antioxidant ATOX1 and low-molecular-weight ligands (Cu-L). These components facilitate mitochondrial transport through Cu chaperones like COX17 [39]. Moreover, ATOX1 can translocate to the nucleus, which aids in delivering Cu to the Cu-transporting ATPase 1 (ATP7A) for subsequent trafficking to the Trans-Golgi Network (TGN) or into vesicular compartments for cellular efflux [40]. Once in the Golgi apparatus, Cu is coordinated with metallothionein, leading to its deposition in lysosomes, thereby safeguarding cells from potential toxicity associated with free Cu [41]. The efflux of Cu from enterocytes occurs via ATP7A, which binds Cu to transcuprein and albumin for transit from the intestine to the liver through the bloodstream [33,42]. Hepatic Cu homeostasis involves finely tuned mechanisms that regulate the secretion of Cu into bile, overseen by hepatocyte activity. Within these hepatocytes, Cu is directed towards the cytosol and mitochondria, where it is primarily integrated into ceruloplasmin before being released into systemic circulation to meet the metabolic demands of various tissues [42,43].

Nano-Cu, when ingested, is absorbed primarily in the gastrointestinal tract through mechanisms that may involve Cu transport proteins, such as Ctr1; however, its precise role in the apical uptake of Cu from the intestinal lumen remains debated [44,45]. Mechanisms such as endocytosis and passive diffusion may facilitate their uptake into enterocytes. After entering enterocytes, nano-Cu may subsequently enter systemic circulation, where it plays essential roles in various physiological processes [45]. Additionally, the physicochemical properties of nano-Cu, including shape, size, and surface chemistry, may significantly affect their ability to cross biological barriers, influencing the bioavailability [46,47,48]. Further, absorption efficiency can be affected by dietary components and the physiological state of the individual [49]. However, the above mechanistic insights may not represent confirmed nano-Cu absorption mechanisms, as the studies did not directly examine nano-Cu absorption by human enterocytes.

Effective regulation between absorption, transport, storage, and distribution of Fe must be maintained by the human body to achieve Fe homeostasis (Figure 2) [37,50,51]. Dietary Fe is predominantly ingested in the oxidized Fe(III) form, which is subsequently reduced to the ferrous Fe(II) form by ferrireductase duodenal cytochrome b (DCYTB). This reduced Fe is then mobilized into enterocytes via the divalent metal transporter (DMT1) [37,52]. Heme Fe absorption occurs through the heme carrier protein 1 (HCP1), establishing a dual pathway for supplying Fe to the cellular Fe pool. Within enterocytes, Fe may be stored in the Fe storage protein ferritin or exported into systemic circulation via ferroportin (FPN1) (Figure 3) [53,54,55].

FPN1 is specifically located in the basolateral membrane of enterocytes, and its activity is modulated post-translationally by hepcidin, which inhibits FPN1’s function and requires hephaestin, a transmembrane Cu-dependent ferroxidase that converts Fe(II) to Fe(III) (Figure 3) [54]. Genetic deletion of FPN1 results in impaired Fe export, leading to excess Fe accumulation within enterocytes [56]. Furthermore, the activity of ferroxidases at the cellular surface is crucial for maintaining FPN1’s stability and Fe export capacity. Dysregulation of Fe export can become detrimental, contributing to various disease states. HCP1 plays an additional role in managing Fe within enterocytes, facilitating the export of Fe and its loading onto transferrin (Tf), which serves as the primary Fe transport protein within plasma [57]. It has been observed that typically less than 50% of the available binding sites on transferrin are occupied by Fe(III), indicating that transferrin saturation levels serve as reliable indicators of both Fe deficiency and overload conditions [58]. As free Fe poses a considerable cytotoxic threat, intracellular Fe transport is regulated by poly(rC)-binding proteins (PCBPs), which guide Fe to ferritin for safe sequestering [59]. Each ferritin molecule has the capacity to store up to 4500 Fe atoms in the ferric (Fe³⁺) state and functions further as a catalyst to reduce ferric (Fe³⁺) to ferrous (Fe²⁺) iron, thus managing Fe availability within the cell [60,61].

The absorption of nano-Fe will likely occur within the duodenum and proximal jejunum, through multiple interconnected mechanisms. Endocytosis may be considered the major pathway, with nano-Fe utilizing vesicular transport, including clathrin-mediated endocytosis (CME), to enter intestinal enterocytes [62]. Additionally, nano-Fe may engage with specific transport proteins such as DMT1, facilitating the uptake of non-heme Fe, specifically in its ferrous form (Fe²⁺) [63,64]. Furthermore, ferritin, a protein complex that stores Fe and releases it in a controlled manner, may also contribute to nanoparticle-based Fe absorption [64]. The physicochemical properties of nano-Fe are another factor determining their absorption efficiency; smaller and positively charged nanoparticles may exhibit enhanced bioavailability compared to larger and negatively charged nanoparticles [65]. Favorable surface ligands (e.g., polysaccharides and proteins) have the potential to further enhance mucoadhesive properties, prolonging the residence time of nanoparticles in the intestines and facilitating sustained release and absorption [66]. Moreover, the interaction with intestinal mucin may also facilitate solubility and promote Fe absorption, ultimately leading to the incorporation of Fe into the systemic circulation via ferroportin after lysosomal dissolution within the enterocytes [65]. However, the above mechanistic insights are hypothesized pathways based on the studies that did not directly investigate nano-Fe absorption by human enterocytes but focused on the phagocytosis of Fe oxide nanoparticles by monocytes, intracellular uptake processes, and associated cytotoxicity [67,68,69,70,71]; thus, may not represent confirmed nano-Fe specific mechanisms.

3. Benefits of Nano–Micronutrients for Human Nutrition

The adoption of nano–micronutrients for Fe and Cu fortification offers multiple benefits over conventional supplementation. One of the primary advantages is the markedly improved bioavailability of these micronutrients [72,73]. Conventional Fe supplements, such as ferrous sulfate (FeSO₄), are often limited by low solubility and adverse gastrointestinal side effects, which reduce patient compliance and overall efficacy [8,9]. In contrast, nano-formulations have been shown to deliver higher concentrations of bioavailable Fe, achieving significant improvements in serum ferritin and hemoglobin levels in both preclinical and clinical models [2,11]. Studies comparing sucrosomial Fe and Fe oxide nanoparticles have demonstrated that nano-approaches can meet the erythropoietic needs more efficiently, while minimizing taste and color alterations in fortified foods [5,8]. Additionally, studies comparing nano-Cu and CuSO₄ similarly found better absorption effect through the nano-approach [74].

Furthermore, nano–micronutrient formulations allow for dose reduction without compromising efficacy. Enhanced absorption means that lower doses are required to achieve the desired nutritional outcomes, thereby reducing the risk of toxicity and manufacturing costs [11,24]. Past in vivo studies on suckling pigs, which physiologically mimic the Fe deficiency often found in low birthweight and preterm infants, show that nano-Fe treatment produces less toxic Fe buildup than conventional supplements, reducing side effects of cardiovascular and respiratory failure [5,75]. This dose efficiency has significant implications for public health, especially in regions where cost constraints limit access to affordable nutrient supplements [2,11]. Increased bioavailability also implies that nano–fortified foods can help address the “hidden hunger” micronutrient deficits prevalent in low- and middle-income countries where dietary diversity is limited [1,76,77].

Another notable benefit is the improvement in organoleptic properties of food when fortified with nano–micronutrients. Because nanoparticles are nearly imperceptible in terms of taste and color, their incorporation into staple foods does not compromise consumer acceptance—a critical factor for the success of food fortification programs [8,24]. Moreover, the stability of nano–micronutrients under various processing conditions is generally higher than that of conventional salts, which often degrade during heat treatment or storage [18,27]. This stability ensures that the fortified nutrient remains effective through the production and distribution chain, thereby improving the nutritional quality of the final product [10,11].

In addition to enhanced bioavailability and stability, nano–micronutrient technologies enable multifunctional benefits. For instance, Fe nanoparticles have been engineered to include antioxidant properties, thereby not only correcting Fe deficiency, but also reducing oxidative stress associated with chronic diseases and offering anti-cancer capabilities [7,29]. Similarly, Cu nanoparticles can be designed to exhibit antibacterial and anti-inflammatory properties, which may provide ancillary health benefits and support overall immune function [6,16]. Such dual-action interventions are particularly attractive in public health strategies aimed at curbing the incidence of both micronutrient deficiencies and infectious disease risks [2,16].

Additionally, the versatility of nano–micronutrient platforms facilitates their incorporation into various carrier systems—including beverages, baked goods, and dairy products—allowing fortification programs to be tailored to culturally specific dietary patterns [10,76,78]. The ability to customize nutrient delivery in this manner is crucial for achieving widespread acceptance and impact on human nutrition, particularly in diverse socio-economic contexts [77,79]. Traditionally, Fe-fortified staple foods (e.g., flour, rice, and beans) have shown variable effectiveness in increasing body Fe levels, highlighting the strong potential of nano–micronutrients to provide more consistent bioavailability [3,80,81]. One study with alginate nano-Fe salt fortified ice cream found that over 90% of the Fe content was being absorbed by the body, with the alginate co-formulation promoting gradual Fe release and absorption [82]. Another study on nano-Fe-fortified wheat biscuits found that the nanoparticles had an antimicrobial property that increased product shelf-life [83]. Multiple studies reported no perceptible sensory differences in nano-fortified foods [82,83,84]. Finally, the sustained release characteristics inherent in many nano-formulations prolong the period over which nutrients are available for absorption, thereby further enhancing the overall efficiency of the fortification strategy [10,13]. An additional summary of the recent findings regarding the nutritional benefits and applications of nano-forms of Cu and Fe, including their ionic supplements, from various study designs is presented in

Table 1. A summary of the recent findings regarding the nutritional benefits and applications of nano-forms of copper (Cu) and iron (Fe), including their ionic supplements, in various study settings. NA denotes not available.

Sample Characteristics	Study Duration	Characteristics and Dose of Nanoparticles Used	Health Outcomes	Reference
8 Wistar rats/group; 5-week-old males	4 weeks	Cu NP powder; 40–60 nm; 6.5 or 3.25 mg/kg BW	Significant improvement in Cu absorption and distribution; enhanced gastrointestinal health was observed by low dose, whereas high dose caused liver toxicity	Cholewińska et al. [85]
10 Wistar rats/group	6 weeks	Cu NP combined with fibers (cellulose, pectin, inulin, or psyllium); 40–60 nm; 6.5 or 13 mg/kg BW	Enhanced antioxidant capacity and reduced oxidative stress markers noted in rats consuming Cu NPs with inulin	Marzec et al. [86]
522 Australian women	Cross-sectional	Dietary intake of ionic Cu and Se was assessed independently	Ionic Cu and Se intakes were independently associated with improved bone mineral density, suggesting a role for Cu in bone health	Pasco et al. [87]
17,310 participants	1997 to 2015, prospective open-cohort study	Dietary intake assessed via survey	Lower cardiovascular risks were associated with moderate ionic Cu intake, highlighting the importance of Cu in overall health	Gan et al. [88]
4 adult mice experimental group and 2 mice control group	24 h	Biodegradable ZnO: Fe nanoparticles; 10 mg/mL; 0.3 mL/mouse	Enhanced Fe bioavailability and safety; nanoparticles effectively delivered Fe to various body tissues	Kiełbik et al. [89]
31,955 children <18 yr-old; review	1973–2013	Standard Fe supplements	Fe supplementation did not result in an excess of severe malaria, and led to fewer anemic children at follow-up	Neuberger et al. [90]
Review	NA	Dietary intake of micronutrients such as Fe and Cu was assessed	Supplementation of specific micronutrients such as Fe and Cu may benefit periodontal therapy, although evidence remains inconclusive.	Berg et al. [91]
Narrative review	NA	Dietary intake of various supplements, including Cu assessed	Supplements, including Cu, can reduce the progression to advanced age-related macular degeneration	Figueiredo et al. [92]

.

Taken together, the benefits of nano–micronutrient fortification are multifaceted. Improved bioavailability, dose efficiency, enhanced stability, and the potential for multifunctional health benefits markedly surpass the capabilities of traditional formulations [2,11,24]. Thus, nano–micronutrients have the potential to revolutionize food fortification strategies and provide a robust solution to combat widespread Fe and Cu deficiencies on a global scale [10,76,77].

4. Challenges and Limitations

Despite the promising potential of nano–micronutrients, several challenges and limitations must be addressed to translate these advancements into widespread public health benefits. One of the principal concerns is the safety and potential toxicity associated with nanoparticles. While many studies have demonstrated improved bioavailability and reduced gastrointestinal side effects, there remain unresolved questions regarding the long-term accumulation of nanoparticles in tissues and their potential to induce oxidative stress or inflammatory responses [7,93,94]. Research shows that while nano-Fe compounds produce benefits like negligible changes in food organoleptic properties (i.e., aroma, appearance, taste, texture) [8], concerns such as nanoparticle-induced cellular damage persist with repeated or high-dose exposure [6,16]. One study found that high doses of Cu nanoparticles in chickens’ drinking water led to Cu accumulation in the small intestine, potentially reducing calcium and zinc absorption [95]. However, another study done in ovo stated nano-Cu had no negative effects on embryo development [96], reinforcing the need for future research to develop a consensus on overall nano-micronutrient impacts.

Moreover, the manufacturing processes for nano–micronutrients require stringent quality control to ensure uniform particle size, surface charge, and solubility. Variability in these parameters can lead to inconsistent absorption and bioactivity, which may undermine the reliability of fortification efforts [11,16,28]. Scaling up production from laboratory settings to industrial volumes also poses challenges, both in maintaining consistency and in ensuring that production methods are cost-effective and environmentally sustainable, especially considering that metals in food waste can pose toxicity risks [10,97]. Advanced synthesis techniques such as green chemistry methods have been proposed to mitigate some of these concerns, yet these technologies are still in the early stages of commercialization [16,94]. As opposed to chemical synthesis, a green method being widely explored is biological synthesis of nano–micronutrients using plants or non-pathogenic microbes as bioreactors [83,98].

Regulatory frameworks also lag technological innovation in the nano–micronutrient arena. Agencies responsible for food safety and nutritional supplements, like the United States’ Food and Drug Administration (FDA) and the European Union’s European Food Safety Authority (EFSA), have been slow to establish specific guidelines for nanoparticles, leading to a degree of uncertainty in terms of permissible exposure limits, labeling requirements, and post-market surveillance [8,10,16]. This regulatory gap is compounded by a lack of standardized testing protocols that can reliably assess long-term safety and bioavailability in human populations, as well as a lack of standardization in nano-micronutrients’ synthesis and characterization [8,10,99]. As a result, widespread adoption of nano–micronutrients in food fortification programs may be impeded until these issues are resolved through more comprehensive risk assessments and international consensus [6,8,16]. Integrated monitoring systems and long-term studies are needed to track the health outcomes associated with nano–fortified food consumption, thereby guiding evidence-based policy decisions [100,101].

Consumer perception poses another significant challenge. Although nano–fortified foods offer enhanced nutritional benefits, there remains skepticism regarding the safety of “nano” in food products. Public awareness and understanding of nanotechnology in nutrition are limited, and adverse publicity regarding the toxicity of certain nanoparticles in other contexts may inadvertently affect the acceptance of nano–micronutrient-based interventions [93,94]. Educational initiatives are needed to communicate the scientific evidence supporting the benefits and safety profiles of nano–micronutrients, yet such efforts are not yet widespread [2,4,6].

Interaction with other dietary components is an additional layer of complexity. Although nano-formulations are designed to overcome the interference of anti-nutritional factors, the presence of compounds such as phytates, polyphenols, and fibers in complex food matrices can still affect the overall bioavailability of the encapsulated nutrients [17,18,19]. Variability in dietary patterns across populations further complicates the prediction of absorption kinetics and efficacy of nano–micronutrients in real-world settings [1,76]. These interactions necessitate rigorous in vitro and in vivo studies, as well as well-designed clinical trials across various diets and demographics, to elucidate the full spectrum of potential impacts [100,101].

Finally, economic and logistical challenges cannot be overlooked. The cost of production for nano–micronutrients may be higher than that for conventional fortificants, and this may limit accessibility in low-income regions where micronutrient deficiencies are most prevalent [77,102]. Investment in research and development, coupled with economies of scale, is required to reduce manufacturing costs and ensure that these advanced supplements can be deployed on a global scale [76,79]. Until such obstacles are overcome, the promise of nano–micronutrients will remain partially unrealized in many parts of the world [10,11,16].

Overall, while nano–micronutrients of Fe and Cu offer significant potential to improve human nutrition, addressing issues regarding safety, production consistency, regulatory uncertainty, consumer acceptance, and economic feasibility is paramount to their successful adoption [8,10,16,93]. Rigorous multidisciplinary research and proactive policymaking must work in tandem to resolve these challenges and facilitate the next generation of micronutrient fortification strategies.

5. Public Health Implications

The adoption of nano–micronutrient technology carries considerable public health implications, particularly in the context of addressing widespread micronutrient deficiencies. Iron deficiency is a leading cause of anemia worldwide, while inadequate Cu intake, although less common, can impair immune function and neurological development [1,6,103]. While the first main diagnosis associated with Cu deficiencies, Menke’s disease, only occurs in about 1 in every 100,000 births, it is usually fatal by early childhood [22,104]. By enhancing the bioavailability of these critical micronutrients, nano-formulations offer the potential to significantly reduce the global burden of anemia, improve maternal and child health, and promote general wellbeing [2,4].

Several intervention studies have demonstrated that fortifying staple foods using nano–micronutrients lead to appreciable improvements in clinical biomarkers. For example, nano-Fe formulations have been shown to elevate hemoglobin and serum ferritin levels in children and pregnant women more effectively than traditional Fe salts [2,3,11]. These findings suggest that nano–micronutrient fortification can contribute to more rapid and sustained improvements in Fe status, thus lowering the risk of adverse outcomes such as developmental delays, impaired immunity, and increased susceptibility to infectious diseases [1,2,4]. Additionally, enhanced Cu bioavailability provided by nano-formulations may further support antioxidant defense systems and enzymatic functions, which are critical for long-term health maintenance [6,16]. Recent research has also begun associating ischemic heart disease, the leading cause of death in the United States, with Cu deficiency and predicts that increased Cu intake would reduce incidence [105,106].

Moreover, the improved organoleptic characteristics of nano–fortified foods—owing to their minimal impact on taste, color, and texture—can lead to higher acceptance by consumers. This is particularly important in cultural contexts where food fortification programs have previously faced resistance due to changes in sensory properties [8,24]. Increased acceptability translates into better adherence to supplementation regimens and more consistent public health outcomes at a community level [10,76].

From an epidemiological perspective, the integration of nano–micronutrients into public health strategies could yield a high return on investment by reducing the prevalence of micronutrient deficiency disorders. In regions where Fe deficiency anemia is endemic (e.g., Latin America and Eastern Africa), the introduction of nano–fortified products may alleviate healthcare burdens, decrease absenteeism in schools, and enhance workforce productivity [1,2,77,81]. In addition, by circumventing the inhibitory effects of dietary anti-nutrients, nano–micronutrient formulations ensure that the intended nutritional benefits are realized, regardless of variations in dietary patterns [17,19]. Avoidance and/or reduction of anti-nutrients, like phytic acid, which is common in beans, is pivotal to consider during nano-fortification in efficiently fighting poor micronutrition [107]. This characteristic is especially significant in low-income settings where diets are often unvarying and of low nutrient density [1,76].

However, the potential public health benefits must be balanced against the challenges of ensuring safety. Regulatory agencies must develop rigorous standards for nano–micronutrient products to avoid inadvertent exposure to harmful nanoparticle residues [6,8]. Equally, public education campaigns are essential to dispel misconceptions about the term “nano” and to build trust in these innovative solutions [93,94]. Integrated monitoring systems and long-term studies are needed to track the health outcomes associated with nano-fortified food consumption, thereby guiding evidence-based policy decisions [100,101].

Table 2. A summary of recent toxicity studies involving iron nanoparticles (FeNPs) and copper nanoparticles (CuNPs), and their potential toxic effects in various model organisms. NA denotes not available.

Model Organism	Dose	Chemical Composition & Size	Toxicity/Health Outcomes	Reference
Sprague–Dawley rats	nose-only exposure, 50 µg/m3 and 500 µg/m3, 3 h/d × 3 d	FeOxNPs (size not specified)	No clinical signs of toxicity, including no significant changes in transcriptomic or metabolomic responses in lung or BEAS-2B cells, to suggest adverse effects	Guo et al. [108]
Sprague–Dawley rats (8-week-old)	50-200 mg/kg/day via oral gavage	CuNP; 82.5 ± 33.4 nm	Significant hepatic oxidative stress, inflammation, and dose-dependent increases in liver toxicity	Tang et al. [109]
Female rats	Intraperitoneal injection of 3 and 50 mg/kg of CuO-NPs for 7 days	CuO-NPs; >20 nm	Induced liver toxicity with diminished PON1 activity; improvement noted with quercetin treatment	Youness et al. [110]
Adult female C57B6 mice	40 μg/m of Fe oxide nanoparticles; 6 h/day, 5 days/week for 5 consecutive weeks	Fe soot (ultrafine particles)	Evidence of neural inflammation and transport to the brain via the olfactory region post-exposure	Hopkins et al. [111]
E. coli-based biosensor	NA	CuNP (size not specified)	CuNPs led to H2O2 generation via release of Cu(I) ions, and caused damage to protein, DNA, and cell membrane in E. coli	Li et al. [112]
Zebrafish	NA	Biogenic CuNP and CuSNP	Reduced oxidative stress in liver and brain acetylcholinesterase activity of CuNP observed with sulfidation; insights into minimizing adverse effects in biological systems	Dharsana et al. [113]
In vitro lung cells	NA	CuNP and CuONP, including micrometer-size Cu particles (size not specified)	Induced a higher degree of DNA damage by nanoparticles compared to micro particles; ion released could not account for the higher toxicity	Midander et al. [47]
Murine macrophage cell line (J774.A1)	5–20 mg/L (ppm)	CuONP and CuSNP; 50 nm, −25 mV	CuONPs induced significantly higher toxicity than CuSNPs after 24 h and 48 h, due to lower Cu bioavailability with CuSNP	Wang et al. [114]
Chlamydomonas reinhardtii	20 mg/L	CuNP; 20–50 nm	Rapid aggregation of nanoparticles into micro-sized particles in algal tris-acetate-phosphate medium; CuNPs were less toxic than CuCl2	Reyes et al. [115]
Zebrafish and Daphnia magna	N/A	CuNP (size not specified)	Nanoparticulate forms of metals were less toxic than soluble ions based on mass added; toxicity was lower for zebrafish than D. magna Induced gill injury and lethality; high levels of reactive oxygen species linked to toxicity were demonstrated.	Griffitt et al. [116]
Mussel (Mytilus galloprovincialis)	10 µg Cu/L; 15 days	CuNP and Cu2+ ions; 31 ± 10 nm, but aggregated in seawater with size of 238 to 338 nm	Significant gill metal accumulation and stress response markers indicating toxic effects were observed for both compounds	Gomes et al. [117]
Earthworms (Eisenia fetida)	up to 65 mg/kg soil	CuNP; <100 nm	CuNPs up to 65 mg kg−1 caused no adverse effects on ecologically relevant endpoints, but may be toxic at higher concentrations (>65 mg Cu kg−1 soil)	Unrine et al. [118]
Zebrafish	Up to 100 µg/L	CuNP; 80 nm	CuNP led to different morphological effects and gene expression patterns in the gill than soluble Cu	Griffitt et al. [119]

summarizes recent toxicity studies involving iron nanoparticles (FeNPs) and copper nanoparticles (CuNPs), their doses used, particle properties, and potential toxic effects in various model organisms.

Cost remains another key factor influencing public health deployment. While nano–micronutrients may have higher production costs than traditional supplements, their superior efficacy and lower dosage requirements may ultimately render them more cost-effective in combating population-scale micronutrient deficiencies [11,102]. Economic analyses indicate that even incremental improvements in a community’s nutritional status, especially among vulnerable groups such as children and pregnant women, produce substantial societal benefits towards areas like improving mortality rates and eradicating malnutrition [2,77]. Food insecurity in marginalized communities across Latin American countries, including Mexico, is profoundly influenced by socio-economic factors, governance, and environmental challenges. Limited access to financial resources constrains the ability of families to purchase nutritious foods, while inadequate infrastructure impedes agricultural productivity and access to markets, exacerbating poverty [120]. Additionally, systemic inequalities, such as land ownership concentration, restrict access to quality agricultural resources and may contribute to food scarcity [121]. Climate change is another major factor that poses significant threats, impacting crop yields and driving up food prices, further promoting food insecurity [122]. Moreover, cultural factors and prevailing dietary habits often lead to the consumption of lower-quality foods, creating a cycle of malnutrition and associated health issues [123]. These elements collectively highlight the need for comprehensive policies aimed at addressing food insecurity through equitable resource distribution and sustainable nutritional and agricultural practices such as nano-enabled food fortification. Given the multitude of socioeconomic advantages nano–micronutrients offer, policy initiatives and international funding mechanisms must support the transition to nano–fortification technologies, particularly in resource-limited settings where nutritional deficiencies are most acute [79,102].

In summary, the public health implications of adopting nano–micronutrients of Fe and Cu are profound. Enhanced bioavailability, improved consumer acceptance, and significant clinical benefits have the potential to transform nutritional intervention programs globally. However, ensuring safety, cost sustainability, and regulatory clarity remain imperative for achieving these benefits on a wide scale [1,2,8,10].

6. Future Outlook

Looking ahead, the field of nano–micronutrient fortification is poised for significant advancement driven by rapid developments in nanotechnology, materials science, and biotechnology [10,11]. Future research is likely to focus on refining synthesis techniques to improve the uniformity, stability, and safety of nano-sized Fe and Cu supplements [16,28]. Advances in green synthesis methods offer the promise of reducing toxic byproducts and lowering production costs, thus making nano–micronutrients more accessible, particularly for low-income communities [11,94,102]. The enhanced bioavailability of nano–micronutrients also reduces the potential for excess nutrients to be excreted in consumers’ excrement, thereby lowering environmental nutrient pollution [124]. Further pertaining to sustainability, plant-based diets with staple crops (e.g., millets and beans) are naturally richer in minerals and commonly grown, making nano-fortification of these crops a green research area of exploration [125,126,127,128].

One promising direction is the development of multifunctional nano-carriers that integrate not only micronutrient delivery but also ancillary benefits such as protection against oxidants and controlled release [13,29]. Such composite delivery systems could be engineered using biodegradable polymers, lipids, or protein-based matrices that are designed to disintegrate under specific gastrointestinal conditions, thereby enhancing the precision and efficacy of nutrient delivery [10,13]. Researchers are also exploring the co-encapsulation of synergistic compounds—for instance, pairing Fe nanoparticles with vitamin C—to further boost absorption and reduce the inhibitory effects of dietary anti-nutrients [19,32].

In parallel, significant effort is being directed toward establishing robust, standardized in vitro and in vivo models to study the long-term safety and bioavailability of nano–micronutrients [8,99,101]. The use of stable isotopes and advanced imaging techniques is expected to provide deeper insights into the absorption kinetics, tissue distribution, and metabolic fate of these nanoparticles [99,100]. Such data will be crucial for informing regulatory frameworks and ensuring that nano–fortification products can be deployed without undesirable health consequences [6,8]. The integration of digital technologies and sensor-based monitoring systems may further enhance the future of nano–micronutrients. For example, real-time tracking of nutrient release and absorption in clinical settings could enable personalized nutrition interventions, allowing professionals to adjust dosages based on individual absorption profiles measured by emerging non-invasive biomarkers [100,101]. Moreover, coupling nano–micronutrients with advancements in precision agriculture and biofortification strategies could yield synergistic benefits by enhancing the micronutrient content of crops at the source, thereby providing a dual approach to combating deficiencies [79,129].

From a regulatory standpoint, international collaboration is essential to establish clear guidelines and best practices for the safe use of nano–micronutrients in food systems [6,8]. Future policies will likely emphasize integrated risk assessment models that combine toxicological data with long-term epidemiological studies. Such frameworks must be dynamic, adapting to technological innovations as well as emerging evidence from continued post-marketing surveillance [8,10].

Public acceptance of nano–fortified foods will also depend on comprehensive education initiatives that involve stakeholders across the value chain—from producers and policymakers to consumers. Transparent communication regarding safety assessments, environmental impact studies, and clinical efficacy data will be paramount for building trust and facilitating the widespread adoption of these novel technologies [2,93,94]. To this end, interdisciplinary collaboration among scientists, engineers, nutritionists, and social scientists will be critical for advancing the field and overcoming current obstacles [10,11,16].

In conclusion, the future outlook for nano–micronutrients of Fe and Cu seems highly promising, with the potential to revolutionize nutritional interventions and substantially improve public health outcomes. Continued investment in research, the development of standardized testing protocols, and proactive policymaking will be essential to fully harness nano–micronutrients’ potential to positively transform human health [10,11,16].

7. Conclusions

Nano–micronutrient fortification represents an advancement in addressing global deficiencies of Fe and Cu. This meta-ethnographic review has elucidated that nano-formulations offer superior bioavailability, controlled release, and enhanced cellular uptake compared to conventional fortificants [10,11]. The mechanisms underlying these benefits—ranging from increased dissolution rates to targeted gastrointestinal release—translate into substantial clinical benefits, including improved hemoglobin synthesis and enhanced immune function [2,15,16]. Despite significant progress, challenges concerning safety, production scalability, regulatory approval, and consumer acceptance remain [6,8,93]. Future research must focus on refining synthesis methods, ensuring rigorous quality control, and establishing comprehensive safety profiles using standardized models [89,99,101,130]. Additionally, integrating nano–micronutrient strategies with broader biofortification and precision nutrition initiatives could yield synergistic benefits and more resilient nutritional security systems [79,129].

Ultimately, the transformative potential of nano–micronutrients extend beyond the laboratory, offering practical solutions to mitigate widespread micronutrient deficiencies and improve public health outcomes around the globe. By addressing current challenges through interdisciplinary research and proactive policymaking, nano–fortification strategies can be safely and effectively implemented, paving the way for a healthier, more nutritionally secure future [2,10,11,16].