Nano-Enhanced Diets: Advancing Metabolic Dysfunction-Related Steatotic Liver Disease (MASLD) – A Review

Introduction

The liver plays a crucial role in protein synthesis, glucose and lipid metabolism, and detoxification.¹ Metabolic-associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease (NAFLD), was recently proposed by global consensus to have its terminology updated to Steatotic Liver Disease Associated with Metabolic Dysfunction (MASLD). This condition is a common liver disorder characterized by fat accumulation exceeding 5% in the liver in individuals who do not consume large amounts of alcohol (ie, less than 30 g/day for men and less than 20 g/day for women).² MASLD represents a significant global health burden; it encompasses a broad spectrum of pathologies, ranging from simple hepatic steatosis to steatohepatitis with varying degrees of fibrosis and liver failure.^3,4 Statistically, the collective prevalence of MAFLD worldwide has surged, with the most recent data showing a figure of 38.20% between 2016 and 2019. The lowest prevalence was recorded in Southeast Asia (24.25%) and the highest in North Africa and the Middle East (42.62%). In Western Europe, the prevalence reached 32.47%.^5,6

The primary cause of this condition is an imbalance between high energy intake and low energy expenditure, which is exacerbated by insulin resistance, obesity, genetic factors, and an unhealthy lifestyle.⁵ To date, despite its increasing prevalence, there are no officially approved pharmacological therapies for the treatment of MASLD.⁷ Therefore, current management focuses on symptomatic and supportive measures (including regulation of blood glucose, lipid levels, and body weight), with lifestyle and dietary changes remaining the mainstay of treatment.^4,7 Despite being the cornerstone of therapy, conventional nutritional interventions often face significant challenges. Beneficial bioactive compounds and nutraceuticals often have limited oral bioavailability, poor stability during gastrointestinal transit, and a lack of proper targeting to the liver. This rapid degradation and inefficient absorption ultimately reduce therapeutic efficacy and consistency of clinical outcomes, necessitating innovative approaches.⁸

Recent advances in nanotechnology have opened up promising new opportunities to overcome these limitations, helping to enhance nutrient absorption, maintain the stability of bioactive compounds, and enable targeted delivery to the liver. However, most of the existing literature reviewed in the field of nanomedicine for liver disease predominantly focuses on pharmacological drug delivery. While important, this focus overlooks the fact that nutritional interventions remain the cornerstone of MASLD management. A significant knowledge gap exists regarding how nanotechnology can specifically optimize dietary and nutraceutical interventions, a critical area that is underserved in the review literature. This review specifically aims to fill this gap, establishing its novelty compared to previous nanomedicine reviews.

In contrast to the vast majority of existing nanomedicine reviews, which predominantly focus on pharmacological drug delivery, this review uniquely fills a critical knowledge gap by centering on nutrient delivery systems (nano-nutraceuticals). This distinction is crucial given that lifestyle and nutritional interventions remain the cornerstone of MASLD management, whereas pharmacological therapies often serve a supportive role. Therefore, this review aims to comprehensively analyze several key aspects. First, we evaluate the underlying molecular and physiological mechanisms, specifically how nanotechnology can exploit specific loopholes in MASLD pathogenesis to enable nutrients to act more effectively on cellular targets. Second, the review examines various nanomaterials used in functional foods and their specific impacts on hepatic steatosis, inflammation, and fibrosis. Finally, we critically assess the challenges regarding production scalability, regulatory approval, cost-effectiveness, and potential nanotoxicity, which remain major hurdles for clinical implementation. By synthesizing current evidence, this review aims to accelerate the integration of nanotechnology into next-generation therapeutic nutritional strategies for metabolic health.

Establishing the Role of Nutraceuticals in MASLD Therapy

MASLD is a progressive disease driven by multiple metabolic and lifestyle risk factors. It progresses through a distinct pathological spectrum, ranging from simple fatty liver (steatosis), which is largely reversible, to steatohepatitis (Metabolic-Dysfunction Associated Steatohepatitis (MASH)), fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC), at which point intervention becomes much more difficult (Figure 1). Understanding this progression is crucial for contextualizing the various therapeutic approaches currently available.

Figure 1 A spectrum of MASLD. MASLD represents a spectrum of disorders ranging from simple steatosis to MASH, ultimately resulting in advanced fibrosis, cirrhosis, and cancer. Immunological mechanisms are involved in the development of MASLD, especially simple steatosis-to-MASH conversion.7

Overview of Metabolic Dysfunction-Related Fatty Liver Disease (MASLD)

Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD) is a clinicopathological condition closely associated with metabolic syndrome, obesity, and diabetes mellitus.⁹ This condition encompasses a broad histological spectrum, ranging from simple steatosis (fat accumulation in ≥5% of hepatocytes) to MASH. Progression to MASH is characterized by hepatocyte injury, inflammation, and ultimately, fibrosis.^10–12

Pathophysiologically, MASLD is driven by metabolic dysregulation, including increased de novo lipogenesis, insulin resistance, and high fructose intake, that leads to steatosis. The transition from steatosis to MASH is triggered by multiple factors, including oxidative stress, mitochondrial dysfunction, and the release of pro-inflammatory cytokines.¹³ The key to intervention is reversibility: in the early stages (steatosis or early MASH), the condition is reversible. However, as advanced fibrosis and cirrhosis progress, liver architectural damage becomes irreversible, making early detection and intervention crucial. If current trends persist, MASH could become the leading indication for liver transplantation, surpassing other etiologies such as viral hepatitis and alcohol-related liver disease. HCC represents the terminal stage of MASLD progression, with emerging evidence implicating immune regulation in the transition from MASH to HCC.⁷

Management of MASLD currently remains a significant clinical challenge. Lifestyle modification (diet and exercise) remains the cornerstone of therapy, but long-term adherence is a major obstacle. Although the recent approval of resmetirom for non-cirrhotic MASLD offers promise, specifically approved pharmacological options remain limited. Various other agents, such as glucagon-like peptide-1 receptor agonists (GLP-1RA) agonists, Sodium-Glucose Transport 2 Inhibitors (SGLT2i), and Thiazolidinediones (TZDs), have shown improvements in liver biomarkers, but often focus on treating comorbidities (such as diabetes) rather than MASLD directly.¹⁴

Current Therapeutic Approaches and Their Limitations

Current management of MASLD focuses on non-pharmacological interventions, with lifestyle modifications (diet and exercise) as the mainstay.^15–17 This approach has proven effective in reducing liver fat and improving insulin sensitivity. However, the biggest challenge is patient adherence. These therapeutic benefits can only be maintained through long-term commitment, which is often difficult to achieve in the real world, creating a need for more accessible supportive interventions.

In recent years, the pharmacological landscape has evolved rapidly, particularly with the advent of GLP-1 agonists (such as Semaglutide) and the approval of Resmetirome for MASH with fibrosis.^12,17 These therapies are very promising, but very targeted: they are intended for patients with more severe disease (confirmed MASH, F2/F3 fibrosis). This leaves the vast majority of patients with early-stage MASLD (simple steatosis) without approved pharmacological options.

For cases of morbid obesity associated with severe MASLD, bariatric surgery (such as RYGB) remains the most effective option for achieving histological resolution.^12,18 However, this is an invasive procedure with significant risks, is only intended for a small proportion of the patient population, and is not a scalable public health strategy for the millions of people with early or intermediate-stage disease.

The combination of these three approaches, such as: lifestyle (difficult to maintain), pharmacology (for advanced disease), and surgery (invasive), creates a significant treatment gap. A significant population suffers from simple steatosis or mild inflammation that does not require drastic interventions such as surgery but cannot rely solely on dietary adherence. This is where formulators and nutrition scientists face the greatest clinical opportunity. Table 1 provides an overview that MASLD treatment is continuously being attempted with various approaches.

Table 1 Developments in MASLD Treatment

This gap opens the door to safe, effective, and long-term nutraceutical interventions. Compounds such as polyphenols, antioxidants, and probiotics offer significant potential for prevention and early-stage management. However, as we will soon discuss, conventional nutraceuticals have their own limitations that hinder their clinical potential.

Pathological Pathways as Targets for Nano-Nutrients

Dysregulation of Lipid Metabolism

A key target in the pathogenesis of MASLD is dysregulation of lipid metabolism. Molecularly, hyperinsulinemia and excess glucose induce the transcription factor Sterol regulatory element-binding transcription factor 1 (SREBP-1c). SREBP-1c then activates the entire de novo lipogenesis (DNL) program, including the key enzymes Fatty Acid Synthase (FASN) and Acetyl-CoA Carboxylase (ACC), which promote new fatty acid synthesis and triglyceride accumulation (steatosis).⁵³ Many nutraceuticals, particularly polyphenols such as curcumin, resveratrol, and Epigallocatechin gallate (EGCG), have demonstrated strong preclinical potential in modulating this SREBP-1c pathway. However, this therapeutic potential is fundamentally hampered in clinical application. These compounds face a critical gap in the form of very poor aqueous solubility and extensive first-pass metabolism, resulting in very low oral bioavailability, often below 1% for curcumin.^54,55 Therefore, the success of nutritional interventions targeting lipogenesis relies heavily on sophisticated delivery systems, creating an urgent need for nanoformulations (such as nanoemulsions or lipid nanoparticles) to enhance solubility, protect compounds, and deliver effective therapeutic doses to the liver.

Oxidative Stress

Excess lipid accumulation in hepatocytes (lipotoxicity) overwhelms the mitochondria, causing electron leakage from the Electron Transport Chain (ETC) and the overproduction of Reactive Oxygen Species (ROS). These ROS then trigger damaging lipid peroxidation, producing highly reactive aldehyde byproducts such as 4-hydroxynonenal (4-HNE).⁵⁶ Vitamin imbalance plays a crucial role in the pathogenesis of MASLD, particularly in exacerbating oxidative stress. There are two main mechanisms:

Direct Antioxidant Deficiency

Vitamins with potent antioxidant activity, such as vitamins C and E, are directly associated with mitigating hepatocyte injury.

Metabolic Cofactor Deficiency

There is a strong correlation between increasing MASLD severity and decreasing serum levels of other key vitamins. In particular, deficiencies of vitamins D, B12, and folate (B9) are frequently reported.

These imbalances (along with other B-complex vitamins such as B6) contribute to the pathological cycle by exacerbating lipotoxicity, systemic oxidative stress, inflammation, and gut microbiota dysbiosis.⁵⁷

Therefore, vitamin supplementation should be viewed not only as nutritional replacement but also as a targeted therapeutic intervention to break this cycle of oxidative stress and inflammation. Interventions with potent antioxidants such as Quercetin, Silymarin, and Vitamin E represent a logical therapeutic strategy to neutralize these ROS. However, their clinical efficacy is hampered by significant critical pharmaceutical gaps: Quercetin and Silymarin are practically insoluble in water, while Vitamin E is a lipophilic compound that requires efficient emulsification for absorption. Therefore, nano-encapsulation platforms are crucial for converting these potent but insoluble antioxidants into stable, biodispersible forms, thereby enhancing their intestinal absorption and protective efficacy.

Inflammatory Pathway Activation

The transition from steatosis to MASH is characterized by chronic inflammation. This process is often described as a “two-step signaling pathway”: Signal 1 (priming) occurs when lipopolysaccharide (LPS) or saturated fatty acids activate Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Signal 2 (activation) occurs when ROS or cholesterol crystals activate the nucleotide-binding oligomerization domain, leucine-rich repeat or pyrin domain-containing 3 (NLRP3) inflammasome.⁵⁸ Nutritional compounds with potent anti-inflammatory properties, such as omega-3 fatty acids (Eicosapentaenoic Acid (EPA)/Docosahexaenoic Acid (DHA)) and some alkaloids (such as berberine), have been shown to modulate the NF-κB and NLRP3 pathways. The critical gap here is twofold: omega-3 fatty acids are highly susceptible to oxidation, which not only reduces their efficacy but also leads to palatability issues (rancid taste/odor). Meanwhile, berberine is known to have very poor oral bioavailability. The nanoscale implications of this are clear: nanoemulsion platforms are crucial for protecting Omega-3s from oxidative degradation and masking their flavor for food fortification, while polymeric nanocarriers are needed to enhance the retention time and absorption of berberine. Emerging therapies such as cytokine inhibitors, antifibrotic agents, metabolic modulators (such as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, Farnesoid X Receptor (FXR) agonists, or GLP-1 receptor agonists), and nutraceuticals show promise in slowing MASLD progression and reducing extrahepatic complications.⁵⁹

Fibrogenesis

Unmanaged chronic inflammation leads to fibrogenesis. Pro-fibrotic cytokines, particularly Transforming Growth Factor-beta (TGF-β) released by stressed Kupffer cells, trigger the activation of Hepatic Stellate Cells (HSCs). These quiescent HSCs transition into active myofibroblasts, which then produce and deposit large amounts of extracellular matrix (primarily type I collagen).⁶⁰ Certain nutraceuticals, particularly silymarin (and its active component, silibinin), have demonstrated promising direct antifibrotic effects by inhibiting HSC activation. However, silymarin is perhaps the most classic example of formulation failure in nutraceuticals. Its main critical gap is its near-zero water solubility, which leads to very poor bioavailability and inconsistent clinical trial results, despite its clear in vitro efficacy. Therefore, advances in silymarin delivery rely almost entirely on nanotechnologies, such as phytosomes or solid lipid nanoparticles (SLNs), which directly overcome this fundamental solubility barrier.

Gut-Liver Axis Dysbiosis

Finally, the pathogenesis of MASLD is closely linked to the gut-liver axis. Gut microbiota dysbiosis contributes to increased intestinal permeability, which allows endotoxin (LPS) translocation to the liver and triggers inflammation through TLR4 activation.⁶¹ Dietary factors greatly influence the microbiota profile; a high-fat and high-fructose diet exacerbates dysbiosis, while a high-fiber and polyphenol diet shows protective effects through restoration of the microbiota and its metabolites (such as short-chain fatty acids (SCFAs), secondary bile acids, and trimethylamine N-oxide (TMAO)).^62–64 A logical intervention strategy is to directly modulate the microbiota through the administration of probiotics and prebiotics. The critical gap for probiotics is unique and absolute: they are fragile living organisms. Most conventional probiotic doses cannot survive the highly acidic pH environment of the stomach. This is where encapsulation (nano- or micro-) becomes crucial.⁶⁵ The use of food-grade polymers such as alginate or chitosan to encapsulate probiotics is crucial to protect them from gastric transit and ensure their proper release at the target site in the intestine.

Microbial enzymes are also essential factors in the development of MASLD and MASH, primarily through their role in the metabolism of steroids (bile acids), choline, and fatty acids. Specifically, these microbial enzymes are key mediators contributing to the metabolism or biosynthesis of these compounds. Dysfunction in these enzymes due to dysbiosis can compromise the intestinal barrier. This increases permeability to bacterial metabolites and liver exposure to microbial-associated molecular patterns (MAMPs), ultimately worsening liver inflammation and fibrosis. A deeper understanding of the role of these microbial enzymes and metabolites may open up opportunities for more precision therapies in the future.⁶⁶

Pharmaceutical Gap as Root of Conventional Nutraceutical Failure

The above analyses consistently demonstrate a significant gap between the in vitro mechanistic potential of many nutraceuticals and their in vivo clinical efficacy. This gap is largely not biological in nature, but rather deeply rooted in pharmaceutical and pharmacokinetic barriers.⁶⁷

The inherent physicochemical properties of these compounds, such as poor aqueous solubility (such as curcumin, silymarin), low gastrointestinal stability (such as probiotics, Omega-3), and inadequate membrane permeability, collectively contribute to their extremely low oral bioavailability.⁶⁸

Management of MASLD often relies on bioactive compounds, although poor solubility and rapid metabolism limit their therapeutic potential. Turmeric and curcumin have been shown to lower key biomarkers, including liver enzymes (such as Alanine Transaminase (ALT), Aspartate Transaminase (AST)), inflammatory cytokines (such as TNF-α, Interleukin-6 (IL-6)), and serum lipid levels (such as triglycerides, Low-Density Lipoprotein Cholesterol (LDL-C)). Furthermore, both have improved insulin resistance and histological scores (such as NAFLD Activity Score - NAS).^69–71 Recent studies resveratrol have identified multiple potential health benefits of RES, including antioxidant, anti-inflammatory, anti-obesity, anticancer, anti-diabetic, cardiovascular, and neuroprotective properties.⁷² Silymarin does consistently show potential in reducing liver enzymes (ALT, AST) and lipid levels, but this is often linked to its ability to modulate inflammation and oxidative stress.⁷³ Supplementation with hesperidin, naringenin, or green tea extract also improves liver enzymes, lipid profiles, and inflammatory cytokines, while genistein has shown no impact on lipid levels.⁵⁴

Therefore, the therapeutic potential of these valid molecular targets remains unrealized. Nanotechnology has emerged as a rationally targeted strategy specifically designed to overcome these fundamental pharmaceutical barriers. Table 2 below presents a critical comparison of these challenges and the proposed nano solutions.

Table 2 Critical Comparison of Pharmaceutical Challenges and the Proposed Nanotechnology Approach

In vivo Evidence for Nano-Nutritional Platforms in MASLD

The clinical potential of conventional nutraceutical interventions for MASLD is fundamentally limited by significant pharmaceutical challenges, primarily poor oral bioavailability and poor gastrointestinal stability. The development of nanotechnology-based delivery systems (NDS) aims to directly address these critical gaps.

Therefore, this chapter specifically presents and analyzes in vivo evidence from preclinical studies. The focus will shift from theoretical discussions of nanoplatforms to specific data demonstrating how nanonutrient formulations quantitatively improve pharmacokinetic parameters and, importantly, produce superior therapeutic efficacy in MASLD models.

Lipid-Based Systems

Lipid-based platforms are the most common and commercially available to address the solubility and bioavailability challenges inherent in lipophilic nutraceutical compounds. Nanoemulsions (NEs), for example, effectively dissolve lipophilic compounds such as curcumin or vitamins in nano-sized oil droplets (<200 nm). This drastically increases the surface area, water dispersibility, and ultimately, intestinal absorption.⁷⁸ A detailed in vivo example can be seen in dihydromyricetin (DMY), a potent hepatoprotective flavonoid whose in vivo efficacy is limited by poor oral bioavailability.⁷⁹ In a high-fat diet-induced MAFLD mouse model, this DMY-hNE formulation not only demonstrated significantly higher intestinal absorption, plasma concentration, and liver distribution compared to free DMY, but also clear therapeutic evidence: mice fed DMY-hNE showed significant reductions in hepatic fat accumulation (steatosis), lobular inflammation, and serum ALT/AST levels. The free DMY group, in contrast, showed virtually no effect.⁷⁹ Similarly, nanoemulsions have been shown to be essential for Omega-3 Fatty Acids. In vivo studies in animal models of MASLD consistently demonstrated that omega-3 nanoemulsions suppress liver inflammatory markers (TNF-α, IL-6) and reduce steatosis more effectively than equivalent doses of conventional fish oil, while addressing oxidation and palatability issues.⁸⁰

In addition to liquid nanoemulsions, liposomes and phytosomes offer another lipid-based platform. These phospholipid vesicles mimic biological cell membranes, enhancing membrane fusion and compound uptake. Silymarin is a classic example of a potent antifibrotic compound that failed clinically due to very poor bioavailability. When formulated as a phytosome (where silibinin is molecularly bound to a phospholipid), its bioavailability is dramatically improved. In an in vivo study in a mouse model of liver fibrosis, administration of silibinin phytosomes resulted in many-fold higher liver concentrations and a significantly stronger antifibrotic effect, as evidenced by reduced collagen deposition and HSCs activation, compared to standard silymarin.⁸¹

Polymer-Based Systems

Moving away from lipid systems, polymer-based platforms, often using food-grade biopolymers such as chitosan, alginate, or starch, excel in protecting fragile compounds from harsh environments and enabling controlled release.^8,82

Curcumin, for example, can be formulated not only in nanoemulsions but also encapsulated in polymer nanoparticles (such as chitosan-based) to increase residence time in the intestinal mucosa. In vivo studies in mice treated with curcumin-chitosan nanoparticles demonstrated a more than 20-fold increase in plasma bioavailability compared to free curcumin.⁸⁰ This pharmacokinetic improvement was directly correlated with greater reductions in hepatic oxidative stress (MDA) markers and improved liver histology in a MASLD model.

The argument for polymer encapsulation becomes even more compelling for highly fragile compounds such as probiotics. Although in vivo MASLD studies directly comparing nano- versus non-nano-based probiotics are still scarce, fundamental gastrointestinal transit studies have proven the principle. In animal models, probiotics nano-encapsulated in alginate/chitosan demonstrated thousands-fold higher survival rates after passage through simulated gastric fluid compared to free probiotics.^74,81 This is crucial prerequisite evidence, indicating that encapsulation is a crucial step to ensure that a viable therapeutic dose reaches the gut.

Nutritional Inorganic Nanoparticles

Finally, there is a distinct category where the nanomaterial itself is the active nutrient, not simply a carrier. Selenium (Se) is a prime example. Selenium is an essential cofactor for endogenous antioxidant enzymes (such as glutathione peroxidase).⁸³ In vivo studies in MASLD mouse models have shown that selenium nanoparticles (SeNPs), often synthesized greenly using plant extracts, are more effective than conventional selenium (such as sodium selenite). SeNP administration demonstrated better restoration of hepatic glutathione peroxidase activity, more significant reductions in oxidative stress (MDA), and greater reductions in ALT/AST levels, often with less toxicity at equivalent doses. A key advantage of SeNPs is their lower systemic toxicity compared to other selenium compounds, even at effective doses, making them a promising candidate for safer therapeutic use in liver-targeted therapies.⁸⁴

Advances in nanotechnology have enabled the optimization of nanoparticle fabrication, composition, morphology, and function for theranostic applications (therapeutic and diagnostic). Many synthetic nanoparticles, natural biomaterials, and bionic nanoparticles have shown particular potential in the diagnosis and treatment of MASH due to their unique properties and superior performance.⁸⁵ As key mediators of liver fibrogenesis, HSCs are a key target for antifibrotic therapy. However, many drugs with potent in vitro activity show limited in vivo efficacy due to low target cell accumulation. Nanotechnology offers a solution to overcome these limitations. Inorganic NPs, such as selenium and zinc oxide, not only function as therapeutic agents and antioxidants but also improve insulin sensitivity.⁸⁶

Mechanism Review: Nanoparticles as Metabolic Modulators in MASLD

Diagnosis of MASH remains a challenge, particularly in differentiating it from simple steatosis before it progresses to irreversible cirrhosis or HCC. The limitations of liver biopsy and conventional imaging have driven the development of nanoformulations for theranostic treatment of MASH. Examples include extracellular vesicle (EV)-based omics analysis and functional Fe₃O₄-based magnetic nanoparticles as magnetic resonance imaging (MRI) contrast agents.⁸⁵

In the early stages of MASLD (steatosis), therapeutic strategies should focus on suppressing de novo lipogenesis and enhancing β-oxidation. Nanoparticle systems targeting SREBP-1c and PPAR-α have shown promising results: siRNA in chitosan nanoparticles reduced SREBP-1c expression by up to 70%, while omega-3 nanoemulsions increased PPAR-α and CPT1 oxidation by up to threefold. Other formulations, such as rosehip oil (REO) and flaxseed oil nanoemulsions, have also been used to enhance the stability and bioavailability of omega-3 fatty acids^87,88 These approaches are effective in restoring lipid homeostasis, although further clinical verification is needed.

In addition to lipid metabolism, mitigating oxidative stress through nanoparticle-enhanced activation of the Nuclear factor erythroid-2 related factor 2 (Nrf2) pathway (such as using gold nanoparticles) is crucial for hepatocellular protection.

As MASLD progresses to MASH, inflammation and fibrogenesis become dominant features. Therapeutic strategies shift toward suppressing the NLRP3 inflammasome (to downregulate IL-1β) and targeting TGF-β signaling (to inhibit HSC activation). Mesoporous silica nanoparticles (MSNs) containing curcumin have demonstrated improved bioavailability and potent NLRP3 inhibition. Synergistic approaches, such as combining MSNs with curcumin with siRNA-TGFβ nanoparticles, offer a promising strategy for simultaneously targeting two key pathways in MASH pathogenesis.⁸⁹

Theranostic approaches are crucial in this dynamic therapeutic transition, enabling the same system to be used for both diagnosis (such as biomarker monitoring) and therapy delivery. A detailed summary of various nanoplatforms targeting core mechanisms of MASLD is presented in Table 3.

Table 3 Summary of the Reported Effects of Nanoparticles in MASLD Management

A synthesis of this Table 3 confirms the main argument: the historical failure of nutraceuticals for MASLD was not a biological failure, but rather a formulation failure. These preclinical data consistently demonstrate how nanotechnology mechanistically overcomes fundamental pharmacokinetic and pharmaceutical barriers.

Formulations such as SNEDDS and albumin particles directly increase oral bioavailability (up to 332% for DHA), resulting in superior efficacy at much lower doses. Meanwhile, platforms such as nanofibers and PLGA solve fundamental solubility and stability issues, protecting active compounds from degradation (such as UV exposure and long-term storage).

More importantly, the field is moving beyond passive enhancement. We are seeing the emergence of “dual therapy” platforms, where the carrier itself is synergistic (such as selenium), and the use of active liver targeting via ligands such as galactose to target the Asialoglycoprotein Receptor (ASGPR) receptor. Collectively, these strategies directly address the multi-hit pathogenesis of MASLD, with data demonstrating simultaneous suppression of lipogenesis (SREBP-1c), inflammation (NF-κB), and oxidative stress (Nrf2).

However, these data also highlight two critical gaps. First, this remarkable preclinical success has not yet translated into clinical applications; the only identified human study is a protocol with no reported results.⁹⁹ Second, nanotoxicity is a real risk, with evidence that some carriers (such as PAA-coated IONs) can induce oxidative stress and inflammation in the liver.¹⁰⁰ This gap between robust preclinical data and scant clinical data, coupled with safety concerns, represents a major translational challenge the field must overcome.

Challenge Future Perspectives for Nutrition Delivery Systems

Despite the enormous potential of nanonutrient platforms demonstrated in in vivo studies, translation from the laboratory to the patient and to the marketplace faces significant challenges. This chapter will not only address the internal challenges facing NDS but also analyze how the evolving landscape of MASLD therapies will shape the future and role of NDS.

Internal Challenges in NDS Translation

The main challenges stem from within the NDS field itself, including clinical evidence, safety, and scalability.

The Clinical Translation Gap From Preclinical to Human

A major current challenge is the limited number of reliable randomized controlled clinical trials (RCTs) in humans.¹⁰¹ Although preclinical data demonstrate promising results, the success of future clinical applications depends heavily on validating that this increased in vivo bioavailability translates into significant clinical outcomes (eg, reduced fibrosis or improved validated NASH scores) in MASLD patients.

Safety & Nanotoxicity Challenges

Concerns about the long-term safety of nanomaterials (nanotoxicity) remain a major obstacle.¹⁰² It is important to distinguish between these types of materials:

• Most of the platforms discussed in this review (such as liposomes, nanoemulsions, phytosomes, chitosan, alginate) are made from materials that are inherently digestible, metabolizable, and GRAS (Generally Recognized as Safe). Food-Grade nanoparticles pose a lower risk.¹⁰³
• Other materials sometimes studied (such as silver, titanium dioxide, or gold nanoparticles) raise concerns about potential bioaccumulation in organs such as the liver or spleen, as they are not readily metabolized by the body. Inorganic/metallic nanoparticles pose a higher risk.¹⁰⁴

A unique challenge for nanonutrients (as opposed to nanomedicines) is that they are intended to be consumed daily over very long periods of time as part of the diet. Data on the toxicological effects of chronic, low-dose consumption of these nanomaterials is still lacking and is a crucial area of research for regulatory and public acceptance.

Production Scalability, Cost, and Stability of Food Matrices

Translating NDS formulations from laboratory batches (mg-scale) to industrial food production (ton-scale) presents significant technical and economic hurdles. Nanoformulations are significantly more expensive to produce than simple powdered extracts. Industry and consumers must be convinced that the increased cost is commensurate with the clinically proven increase in efficacy.¹⁰⁵ Furthermore, the stability of NDS in complex food matrices (such as ensuring nanoemulsions do not separate or precipitate in yogurt or juice during shelf life) remains a significant food engineering challenge.

Shaping the Future of NDS in the MASLD Era

The internal challenges previously outlined are not merely theoretical; rather, they are a direct consequence of the substantial public and commercial demand for precision nutrition.¹⁰⁶ The global market for nanotechnology-based nutraceuticals, for example, is projected to grow rapidly at a CAGR of over 9%, reflecting a clear societal trend toward preventative health solutions.¹⁵ This market push creates a crucial context for the future of NDS: it provides commercial incentives to address scalability and safety challenges, while also increasing the urgency to integrate NDS into the emerging of new MASLD therapies. The future of NDS will not occur in a vacuum. It will be directly shaped and driven by other breakthroughs in the MASLD field, creating both new challenges and opportunities.

New Nomenclature (MASLD/MetALD) as an NDS Opportunity

The shift in terminology from NAFLD to MASLD has significant implications. In particular, the introduction of the category MetALD (Steatotic Liver Disease Associated with Metabolic Dysfunction and Alcohol Consumption) is crucial. This category formally recognizes a very large patient population previously excluded from NASLD diagnosis and clinical trials: those with metabolic dysfunction (obesity, T2DM) but also moderate alcohol consumption (such as 20–50g/day for women, 30–60g/day for men). This MetALD group suffers from a “double-hit” of metabolic stress and alcohol toxicity.^7,107 This creates a new niche and clinical need where potent hepatoprotective nutraceutical interventions, such as nano-silymarin or nano-antioxidants, are highly relevant as safe, supportive therapies for this underserved population.

Impact of New Pharmacotherapies on the Role of NDS

The approval of the first pharmacotherapies targeting MASH (such as Resmetirom) does not obsolete NDS; rather, it creates and clarifies a new niche for NDS. These drugs are often expensive, intended for MASH patients with significant fibrosis (stage F2/F3), and have potential side effects.¹⁰⁸ This new landscape opens up at least two strategic roles for NDS:

1. For the much larger population of patients with early-stage MASLD (simple steatosis) who are ineligible for aggressive pharmacotherapy, NDS serves as a lower-cost preventive intervention.¹⁰⁹
2. As adjunct therapy, anti-inflammatory or anti-oxidative NDS (nutrient delivery systems) can be used in conjunction with pharmaceutical drugs to manage liver stress, potentially improving outcomes or even reducing side effects.¹¹⁰

Convergence of NDS with Non-Invasive Diagnostics & AI

Currently, one of the biggest barriers to proving NDS efficacy is the need for invasive, expensive, and risky liver biopsies. Therefore, rapid developments in non-invasive biomarkers (from blood) and AI-based diagnostics (imaging, elastography) are crucial for the future of NDS.¹¹¹ These diagnostic tools will enable NDS clinical trials to be cheaper, faster, larger, and more ethical. AI will not only diagnose MASLD but will also be an essential validation tool that can objectively monitor and prove that, for example, your nano-curcumin actually reduces steatosis or liver stiffness over time, providing the necessary evidence for regulatory approval.

Green Nanotechnology as a Path to Implementation

Given the challenges, such as cost, safety, and scalability, the most realistic future for NDS for mass nutritional applications likely lies not in exotic synthetic materials, but in green nanotechnology.¹¹² This means focusing on the development of sustainable, low-cost, and GRAS-approved platforms derived from natural sources. These include biopolymers such as chitosan (from shrimp waste), alginate (from seaweed), zein (corn protein), and modified starch. These “food-grade” platforms represent the most likely bridge to bring nanonutrients from the laboratory to the supermarket shelf and ultimately to the patient.

Conclusion

Nutritional intervention remains the cornerstone of MASLD management, yet the clinical efficacy of key nutraceuticals (such as curcumin and silymarin) has historically been hampered by poor oral bioavailability. This critical review concludes that nanotechnology-based delivery systems (NDS), specifically nanoemulsions and phytosomes, offer a potent mechanistic solution to overcome this pharmacokinetic gap, translating into superior therapeutic efficacy in preclinical models. However, clinical translation faces significant hurdles regarding long-term safety data (nanotoxicity) and production scalability. Consequently, the future research agenda must prioritize: (1) the advancement of “green nanotechnology” utilizing safe, cost-effective “food-grade” (GRAS) materials, and (2) the integration of personalized therapeutic strategies that account for patient stratification to maximize clinical outcomes in this heterogeneous disease.