Abstract
Obesity treatment is entering a new era with the advent of multifunctional nanomaterials capable of precise biological intervention. This review highlights their pivotal role in overcoming key therapeutic limitations, including poor targeting, systemic toxicity, and low bioavailability. Based on the systematic analysis of lipid metabolism, we propose five strategic intervention points: reducing lipid intake, interfering with absorption, inhibiting storage, promoting consumption, and remodeling the adipose tissue microenvironment. Furthermore, we examine the application of diverse nanoplatforms in these therapeutic strategies, ranging from inorganic or polymeric nanoparticles to natural biopolymer-based nanomedicine, and demonstrate their potential in realizing precise targeting and transdermal drug delivery. By integrating mechanistic insights with advanced nanomaterial design, this work not only outlines a systematic framework for obesity nanomedicine, but also accelerates the translational path toward precision anti-obesity therapies.
Keywords: Obesity treatment, Nanomaterials, Lipid metabolism, Targeted delivery
Graphical abstract
Highlights
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Obesity and its complications are driven by dietary lipid metabolism.
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Nanomaterials can achieve targeted obesity treatment through five strategies.
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Nanomaterials can advance targeted and transdermal delivery system.
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Nanomaterials can synergize with PDT, PTT, SDT to improve anti-obesity efficacy.
1. Introduction
As an important factor affecting the health of human body, obesity is becoming more and more prevalent. According to the latest 2025 World Obesity Atlas, it is predicted that by 2030, nearly 3 billion adults worldwide, approximately 50% of the global adult population, will be affected by obesity [1]. Obesity is closely linked to the occurrence and progression of various diseases, such as cardiovascular diseases, diabetes, gastrointestinal disorders, and cancer. Among these, cardiovascular diseases (CVD) are the leading cause of death globally, and multiple studies have proven that obesity is an independent risk factor for several CVDs, including ischemic heart disease, atherosclerosis, aortic valve stenosis, and stroke [[2], [3], [4]]. Type 2 diabetes (T2D) is the most common comorbidity associated with obesity, with patients suffering from severe obesity having a 70-75% lifetime risk of developing T2D, while 80% of T2D patients also exhibit obesity symptoms [5,6]. In addition, there is a strong association between obesity and gastrointestinal (GI) diseases like metabolic dysfunction-associated steatotic liver disease (MASLD) and inflammatory bowel disease. The prevalence of MASLD among overweight patients is about 70-75%, making overweight a key criterion for diagnosing MASLD [7]. The rising global prevalence of obesity not only correlates with increased incidence of associated comorbidities, but also contributes to higher mortality and disability rates, imposing a significant financial burden on healthcare systems worldwide [[8], [9], [10]]. In a word, obesity is rapidly evolving into a global public health crisis that requires urgent attention and intervention.
However, current obesity treatments are neither widely nor effectively applicable in clinical interventions. The commonly used clinical treatment methods can be divided into four types: lifestyle changes, pharmacotherapy, surgical treatment and local fat reduction (Table 1). Lifestyle changes focus on dietary control and moderate exercise, which are suitable for most obese patients but heavily depend on patient compliance. The majority of obesity treatment medications act as appetite suppressants targeting the central nervous system (CNS), which often accompanied by psychiatric side effects [11,12]. A few drugs, such as Orlistat, act on digestive enzymes in the GI tract, but it can also lead to GI adverse effects including diarrhea and abdominal pain. Currently, some incretin receptor agonists are emerging as star drugs for the treatment of obesity and diabetes. For example, GLP-1 analogs like Liraglutide and Semaglutide [13], as well as dual or triple incretin receptor agonists such as Tirzepatide, Mazdutide, and Retatrutide [14], can simulate the effects of GLP-1, GIP, and GCG, activating their corresponding receptors to suppress appetite and regulate insulin secretion. But the peptide structure of these drugs limits their oral absorption efficiency, and they may also cause some GI side effects. Bariatric surgery demonstrates superior therapeutic efficacy, yet it is also associated with higher surgical risks and is not suitable for most patients with mild to moderate obesity [15]. In contrast, the systemic side effects caused by local fat reduction methods are relatively minimal. However, their limited treatment scope prevents them from improving whole-body energy metabolism and they are ineffective against visceral fat, which poses greater health risks [16]. Hence, there is an urgent need to develop novel obesity treatments to control the further expansion of obese epidemic.
Table 1.
Current clinically employed treatments for obesity.
| Therapeutic Pathway | Drug/Method | Mechanism of Action | Limitations |
|---|---|---|---|
| Lifestyle modification | Diet control and moderate exercise | Reduces energy intake and increases energy expenditure. | Highly dependent on patient compliance |
| Pharmacotherapy [11,24] | Phentermine-Topiramat (Qsymia) | Synergistic appetite suppression: Phentermine can increase the secretion of epinephrine in the hypothalamus, Topiramat can increase satiety and energy expenditure | Side effects: Insomnia, constipation, dizziness, paresthesia, dysgeusia, and dry mouth |
| Naltrexone-Bupropion (Contrave) | Synergistic appetite suppression: Naltrexone is a norepinephrine and dopamine reuptake inhibitor, Bupropion is a μ-opioid receptor antagonist. | Side effects: Nausea, constipation, headache, dizziness, vomiting, insomnia, dry mouth and diarrhea | |
| Orlistat (Xenical) | Pancreatic lipase inhibitor, which can interfere with lipid absorption. | Gastrointestinal side effects: diarrhea, flatulence and abdominal pains | |
| GLP-1 receptor agonists: Liraglutide and Semaglutide etc. |
Promote insulin secretion, delay gastric emptying, and suppress appetite. | They cannot be administered orally and may cause gastrointestinal side effects like nausea, diarrhea, constipation, and vomiting. | |
| Dual/Triple incretin receptor agonists: Tirzepatide (GLP-1R + GIPR), Mazdutide (GLP-1R + GCGR), Retatrutide (GLP-1R + GCGR + GIPR) | By mimicking the effects of incretin including GLP-1, GIP, and GCG, it promotes insulin secretion, suppresses glucagon secretion, regulates hepatic glucose and lipid metabolism, and effectively exerts synergistic anti-obesity effects. | Similar to GLP-1 analogs, most drugs are difficult to administer orally, and are accompanied by gastrointestinal side effects such as nausea, vomiting, and constipation. | |
| Surgical therapy [25] | Laparoscopic Roux-en-Y gastric bypass | Restricting food intake and absorption by reconstructing the digestive tract structure. | High threshold: Only suitable for obese patients with a BMI >40 kg/m2, or a BMI >35 kg/m2 accompanied by at least one serious comorbidity. And high risk: The mortality rate is approximately 0.2%-0.4% [15]. |
| Laparoscopic sleeve gastrectomy | Transecting the stomach vertically and creating a sleeve to increase stomach volume. | ||
| Local fat reduction | Injection lipolysis: Deoxycholic acid injection. | Adipocyte membrane dissolving agent, which destroys adipocytes, achieving local fat reduction at the injection site. | It can induce adverse reactions such as pain and swelling at the injection site, with some patients experiencing mandibular nerve paralysis or skin necrosis [26,27]. |
| Cryolipolysis | Utilizing local low-temperature treatment to induce the browning and death of adipocytes. | Local frostbite, numbness, and in some cases, adverse effects such as paradoxical adipose hyperplasia and adipose tissue fibrosis [28]. |
While obesity is influenced by various factors such as diet, genetics, environment, and psychology [17,18], its root cause lies in the imbalance between energy intake and expenditure, leading to excess energy being stored as lipids in the adipose tissue (AT). However, current clinical treatments mainly focus on controlling the intake of energy substrates, particularly dietary lipids, overlooking the regulation of the entire process of metabolism of these substrates. This is not only due to the limited understanding of obesity mechanisms, but also because the inherent difficulty in achieving complete targeting with current therapeutic approaches. Nanomaterial offers an effective solution to the targeting problem, and it also demonstrates significant potential in enhancing drug stability and enabling controlled release [19,20]. In recent years, several studies have reviewed the application of nanomaterials in anti-obesity treatment and drug delivery [[21], [22], [23]], but few studies have systematically reviewed the targeted applications of nanomaterials in the various stages of lipid metabolism. Therefore, in this article, we aim to analyze the entire process of dietary lipid absorption and storage in the body, to identify strategies that can be applied to anti-obesity treatment. Additionally, we will review the recent applications of nanomaterials in these strategies, providing a foundation for the development of novel anti-obesity treatments.
2. Lipid metabolism process and its role in obesity pathogenesis
The energy absorbed by human body is primarily in the form of carbohydrates, lipids, and proteins. Since the absorption processes of these nutrients are largely similar, and excess nutrients are ultimately converted into triglycerides and stored in adipocytes. In this context, we mainly focus on lipids, providing a concise analysis of the entire process of dietary lipid digestion, absorption, distribution, storage, and utilization in the body (Fig. 1). Additionally, we explore the relationship between excessive lipid accumulation (i.e., obesity), the microenvironment of AT, and the onset of obesity-related complications.
Fig. 1.
Schematic diagram of the lipid metabolism process. Including: lipid intake, absorption, distribution, accumulation, and changes in adipose tissue microenvironment (Created in https://BioRender.com). Abbreviations: HSL: Hormone-Sensitive Lipase; DAG: Diacylglycerol; DGAT1: Diacylglycerol O-Acyltransferase 1; TAG: Triacylglycerol; CD36: Cluster of Differentiation 36 (also called Fatty Acid Translocase); FABP: Fatty Acid-Binding Protein; FATP: Fatty Acid Transport Protein; TCA cycle: Tricarboxylic Acid Cycle.
Lipid Digestion: Although there are a variety of dietary lipids absorbed by the human body, they are all composed of triglycerides. Upon ingestion, dietary lipids are initially broken down into lipid aggregates during the chewing process and through the catalyzation of lingual lipase. Subsequently, they are further degraded into smaller lipid particles under the influence of gastric acid, forming a mixture with gastric contents to create chyme. Finally, in the small intestine, pancreatic lipase catalyzes the hydrolysis of triglycerides into free fatty acids and monoglycerides [29].
Lipid Absorption: The digestive products of lipids are absorbed by the epithelial cells of the small intestine, where they are re-esterified into triglycerides within the endoplasmic reticulum. Subsequently, these triglycerides, along with apolipoproteins, cholesterol esters, and phospholipids, are assembled into chylomicrons, which are then released into the bloodstream [30].
Lipid Distribution: Chylomicrons are transported through the bloodstream to various tissues. In the capillaries, they are hydrolyzed by lipoprotein lipase into free fatty acids and glycerol. The fatty acids may be oxidized as fuel to provide energy to tissue cells or stored as triglycerides in adipocytes [31,32]. The remaining chylomicrons are then transported to the liver, where they undergo further processing and recycling.
Lipid Storage: When dietary lipid intake exceeds the body's energy requirements, excess fatty acids are stored as triglycerides in AT, primarily within white adipose tissue (WAT), which serves as the main site for lipid storage [33]. WAT is distributed throughout the body and is classified into subcutaneous WAT and visceral WAT. Although visceral WAT represents a smaller proportion, it exerts a more significant impact on health [34,35]. As triglycerides accumulate, WAT undergoes expansion through both hyperplasia (an increase in cell number) and hypertrophy (an enlargement of cell size), which collectively manifest as obesity at the macroscopic level [36].
Lipid Utilization: The body will secrete adrenaline and norepinephrine if energy is urgently needed, which activate β-adrenergic receptors on the surface of WAT cells. This activation initiates the cAMP-PKA signaling cascade, leading to the phosphorylation of hormone-sensitive lipase (HSL). Consequently, HSL catalyzes the breakdown of triglycerides into free fatty acids within WAT cells to provide energy for the body [37].
An increasing number of studies have shown that the continuous expansion of AT is accompanied by chronic inflammation and exacerbated oxidative stress [[38], [39], [40]]. Macrophages are the most abundant immune cells in AT, but in the AT of obese individuals, pro-inflammatory M1 macrophages significantly outnumber anti-inflammatory M2 macrophages [41]. This imbalance not only leads to increased release of pro-inflammatory cytokines like TNF-α and IL-6, and decreased levels of anti-inflammatory cytokines like IL-10 and IL-4, but also results in dysregulated adipokine secretion, including elevated leptin and reduced adiponectin levels. Concurrently, the expansion of AT is associated with a pro-inflammatory microenvironment characterized by AT fibrosis, impaired angiogenesis and hypoxia [42]. Furthermore, AT expansion also imposes extensive metabolic stress on mitochondria, and combined with local hypoxia, it enhances the generation of reactive oxygen species (ROS), thereby triggering oxidative stress [43].
The chronic inflammatory and oxidative stress state of AT is a major driver of the progression of multiple obesity-related complications, including T2D, CVD, and MASLD. In the case of T2D, abnormal secretion of pro-inflammatory cytokines and adipokines can inhibit the activity of insulin receptors and impair insulin signaling pathways [44,45], while aggravated oxidative stress further interferes with the expression of glucose transporters [46]. These factors contribute to the development of insulin resistance (IR) and even the progression to T2D. For CVD, the pro-inflammatory cytokine TNF-α significantly upregulates the transcytosis of low-density lipoprotein (LDL) across vascular endothelial cells, and promotes its retention within the vascular wall, thereby facilitating the development of atherosclerosis and related diseases [47]. Moreover, the downregulation of adiponectin, a protective adipokine against CVD, is also a contributing factor in the onset of cardiovascular diseases [48]. The relationship between MASLD and obesity is more direct. As MASLD is characterized by ectopic deposition of AT in hepatocytes, leading to structural and functional alterations of the liver [49]. Obesity inevitably leads to hypertrophy of visceral adipocytes, particularly in the liver, and the pro-inflammatory microenvironment within AT further accelerates the progression of MASLD [50].
3. Nanomaterial-enabled advanced drug delivery systems
Oral and injectable routes are the two most prevalent administration methods in obesity treatment, but both of them have some disadvantages. Oral administration as the most efficient local GI delivery method, plays an important role in regulating the intake and absorption of dietary lipids. Nevertheless, when adapted for systemic delivery, oral administration encounters reduced drug absorption efficiency due to the first pass effect, as well as significant off-target effects leading to adverse reactions. Moreover, oral delivery is unsuitable for metabolically unstable drugs, such as peptides and proteins. Injectable administration is applicable for both local (e.g., intraperitoneal or intramuscular) and systemic (e.g., intravenous) delivery. However, the complexity of injection techniques and the potential risk of infection limit its widespread use in obese patients. To overcome these limitations, extensive research has focused on utilizing nanomaterials to enhance drug targeting capabilities and facilitate transdermal delivery, offering promising alternatives for obesity treatment.
3.1. Nanomaterial-based targeted drug delivery system
The pathological core of obesity lies in the expansion and dysfunction of AT, positioning AT as a critical target for the treatment of obesity and its complications. Specifically delivering anti-obesity drugs to AT can significantly enhance therapeutic efficacy, reduce the systemic drug dosage, and minimize off-target side effects. This approach is crucial for improving the therapeutic window and clinical safety of the drugs.
The distinctive physiological characteristics of AT in obese individuals provide a foundation for the selective targeting by nanomaterials with specific properties. These features include: (1) Altered vascular permeability: The rapid expansion of AT induces hypoxia, leading to angiogenesis and generating an Enhanced Permeability and Retention (EPR) effect akin to that observed in tumor tissue [51]. (2) Negative charge: The extracellular matrix in the AT of obese individuals contains higher levels of negatively charged glycosaminoglycans, imparting a net negative charge to AT [52,53]. (3) Lipophilic nature: Mature adipocytes contain large lipid droplets composed of hydrophobic components, such as triglycerides and fatty acids, creating an enriched environment for lipophilic substances. (4) High expression of specific molecular targets: Certain proteins, such as Prohibitin [54] and Adipocyte Plasma Membrane Associated Protein (APMAP) [55], are overexpressed on the endothelial cells of AT vasculature and the membranes of adipocytes, providing viable targets for molecular recognition-based active targeting.
Owing to the EPR effect in AT, nanoparticles (NPs) can be passively targeted to the AT of obese individuals and remain retained over extended periods. As early as 2012, Hideyoshi Harashima's team demonstrated that PEGylated liposomes could selectively accumulate in the AT of obese mice, a phenomenon not observed in healthy mice, thereby confirming that PEG modification enhances the passive targeting capability of nanomaterials via the EPR effect [56]. In subsequent studies, Xue et al. utilized PLGA-b-PEG copolymers to encapsulate the anti-obesity drug Rosiglitazone (Rosi) [57]. Compared to its free form, Rosi-NPs exhibited marked tumor-targeting efficacy, further confirming the passive targeting potential of NPs through the EPR effect.
Based on the negative charge and lipophilic nature of AT, positively charged or lipophilic nanomaterials can selectively accumulate within AT. In 2022, Wan et al. first reported that cationic polymers can specifically accumulate in AT [58]. They found that the third-generation cationic PAMAM (P-G3) targeted WAT, disrupted lysosomal function, and inhibited lipogenesis by downregulating the mTOR and NAD signaling pathways, thereby demonstrating therapeutic efficacy for obesity. Interestingly, this study also found that P-G3 NPs preferentially targeted visceral WAT (such as epididymal WAT, eWAT), over subcutaneous WAT (such as inguinal WAT, iWAT), offering a promising strategy for the treatment of visceral obesity (Fig. 2). A growing number of positively charged nanomaterials, including chitosan and cationic albumin, have since been shown to exhibit selective targeting effects on WAT [59,60]. Similarly, lipophilic drugs also exhibit passive targeting capabilities in adipocytes. Michelle et al. demonstrated that small-molecule probes with aggregation-induced emission (AIE) properties could specifically target lipid droplets in mature 3T3-L1 adipocytes, enabling enhanced luminescence and selective imaging of lipid droplets [61].
Fig. 2.
The cationic polymer P-G3 NPs are capable of targeting visceral AT and inhibiting lipid accumulation. a. Schematic of the positively charged P-G3 structure and negatively charged extracellular matrix (ECM) of AT. b. Ex vivo imaging of Cy5 fluorescent signal of tissues after incubating with Cy5-labelled P-G3 for 45 min. c. After eight weeks of HFD feeding with Vehicle or P-G3 injection, the weights of eWAT, iWAT, and liver in C57BL/6 mice, as well as the histological analysis (H&E staining) results of eWAT and iWAT [58]. Copyright © 2022, Published by Springer Nature.
Prohibitin plays an important role in regulating cell survival and growth, and is highly expressed on the vascular endothelial cell membranes within WAT, where it is recognized and bound by the Adipose Homing Peptide (AHP, CKGGRAKDC) [62]. This characteristic has led to the widespread application of AHP modification in the active targeting delivery of anti-obesity nanomedicines. In a study by Ma et al., AHP was employed to surface-functionalize NPs composed of the photosensitizer PPIX and the anti-obesity drug Baicalin (Baic) [63], thereby enabling targeted PDT and browning of WAT. Due to the selective targeting capability of AHP, the modified NPs achieved significantly higher accumulation in AT and exhibited more potent effects compared to unmodified NPs. As one of the most widely used AT-targeting ligands, AHP will also be frequently discussed in this review.
Aptamers are DNA or RNA oligonucleotides that exhibit high specificity for recognizing targets such as cells and proteins. Adipo-8, a specific aptamer targeting APMAP on the membranes of mature adipocytes, serves as a prominent ligand for active AT targeting [55]. The use of Adipo-8 aptamer alone has been shown to improve lipid deposition, thereby promoting weight loss in mice [55]. Xu et al. demonstrated that DNA nanoflowers developed with the Adipo-8 aptamer could selectively deliver Allicin to WAT cells, effectively inducing the browning of WAT [64]. Moreover, Adipo-8 has been utilized for surface modification of liposome encapsulated nordihydrocapsaicin NPs, significantly boosting the active targeting capability of liposomes [65].
3.2. Nanomaterial-based transdermal drug delivery system
Transdermal drug delivery systems work by transporting drugs or NPs through the skin into local tissues or the systemic circulation. It allows for direct delivery to subcutaneous AT, a key site for lipid storage and a primary target for many anti-obesity agents. Meanwhile, transdermal delivery is a non-invasive, pain-free, and user-friendly method, offers advantages in patient self-management [66]. Compared to the GI irritation induced by oral administration, and the needle phobia associated with injectable administration [67,68], transdermal delivery offers a more convenient alternative, with relatively fewer side effects.
Traditional transdermal drug delivery systems, such as creams, gels, and patches, rely on the concentration gradient across the skin to drive passive diffusion, and placing high demands on the lipophilicity of drugs [69,70]. To further enhance permeation efficiency, nanotechnologies such as liposomes [71], lipid NPs [72], and glycerosomes [73] have been incorporated into transdermal delivery systems for hydrophilic drugs [74]. Taking deoxycholic acid (DCA) as an example, it can induce lysis and necrosis of adipocytes, and its injectable form Kybella® has been approved by the FDA in 2015 as the first localized lipolytic agent [75]. However, the strong hydrophilicity of DCA limits its skin permeability, and oral administration can disrupt gut microbiota, leading to intestinal inflammation [76]. To overcome these challenges, Hwajun Jeong et al. developed a 4-CPMD conjugated polymer by combining hydrophilic 4-arm PEG with hydrophobic dimethylsiloxane, enabling the encapsulation of DCA and its enhanced transdermal delivery [77]. Compared to free DCA, which showed no significant weight loss effects, the DCA@4-CPMD gel notably improved the skin permeability, resulting in a reduction of both body weight and WAT weight in high fat diet (HFD) induced obese mice (Fig. 3).
Fig. 3.
Application of gel nanotechnology in transdermal anti-obesity drug delivery systems. a. Schematic diagram of the preparation and administration process of DCA@4-CPMD. b. In vivo skin permeability efficiency analysis results of 4-CPMD. CLSM images of cryo-sectioned mouse skin after treatment with Oil Red O (OR) and OR-encapsulated 4-CPMD. Scale bar: 400 μm. c. Tissue weight changes over the experimental period for each group [77]. Copyright © 2025, Published by Elsevier B.V.
Nonetheless, passive diffusion consistently encounters the stratum corneum barrier, which severely restricts the permeation efficiency of most therapeutic agents. To solve this problem, researchers have developed a range of physical and chemical approaches to enhance the active diffusion of drugs across the skin [[78], [79], [80]]. For example, iontophoresis employs a mild electric current applied to the skin surface, to facilitate the penetration of charged drug molecules [[81], [82], [83]]. Chen et al. encapsulated insulin within nanocarriers of different surface charges, and utilized iontophoresis to boost delivery efficiency [84]. Their findings revealed that small, positively charged NPs exhibited accelerated permeation kinetics, attributed to favorable electrostatic interactions with the skin barrier. Nevertheless, the utility of iontophoresis remains constrained by its reliance on limited penetration pathways such as hair follicles and sweat glands, which ultimately restricts its overall enhancement efficacy. As a result, this technique has yet to achieve broad adoption in transdermal drug delivery applications.
Microneedles (MNs) represent the most widely utilized physical enhancement system for transdermal drug delivery [85,86]. This is a minimally invasive transdermal drug delivery patch composed of micro-scale arrays, with needle lengths ranging from 100 to 1500 μm. These MNs are designed to penetrate the stratum corneum and epidermis without reaching the dermis, enabling painless transdermal drug administration [87]. Depending on their mode of action, MNs can be categorized into five types: solid, coated, hollow, dissolving, and swelling MNs [88]. Dissolving MNs, in particular, are made from various biocompatible and biodegradable materials such as hyaluronic acid (HA), carboxymethyl cellulose (CMC), and polyvinyl alcohol (PVA), which rapidly dissolve upon skin penetration, releasing the encapsulated drug [89]. These properties make dissolving MNs ideal for the daily management of obesity. As an emerging transdermal delivery technology, MNs have gained significant traction in obesity treatment in recent years [74,90].
However, the efficacy of transdermal drug delivery systems is often influenced by individual differences and environmental factors, which limits their general applicability in obesity treatment [91]. For instance, compared to adults, infants have an underdeveloped skin barrier, while elderly individuals experience a decrease in skin moisture and changes in lipid composition, leading to variations in drug permeability among different age groups [92,93]. Moreover, in patients with severe obesity, the significant thickening of subcutaneous AT further affects the absorption, distribution, and other pharmacokinetic properties of the drug [94]. And variations in skin thickness, hydration, and follicular density across different body regions of the same individual may impact drug penetration efficiency and the appropriate MN length [95]. Therefore, considering these factors, the development of personalized transdermal delivery systems tailored to different ages, obesity levels, and body regions holds great promise as a key avenue for advancing transdermal treatments for obesity.
Overall, targeted drug delivery systems as a tool, can effectively reduce the systemic toxic side effects of drugs. Nanomaterials, with their size advantages and easily modified surfaces, offer promising possibilities for achieving precise targeted delivery. However, various targeted delivery technologies are still in the early stages of research, with no mature solutions yet entering clinical translation. Transdermal drug delivery, as the third major route of obesity treatment following oral and injectable methods, represents a localized drug delivery strategy that targets subcutaneous AT. Recent research supports its potential in minimizing systemic drug toxicity [96,97]. MNs have become a research hotspot, effectively overcoming the limitations of traditional patches, such as low penetration efficiency and the stratum corneum barrier. Nevertheless, MNs still faces challenges, including complex fabrication processes, high costs, and insufficient foundational research, making it some distance from achieving commercialization.
4. Classification of nanomaterials for precision obesity treatment
There is a wide variety of nanomaterials that can be applied to obesity treatment. Based on their composition, they can be simply classified into inorganic and organic nanomaterials. Inorganic nanomaterials can further be subdivided into metal-based and nonmetal-based types. These nanomaterials exhibit excellent photothermal effects, catalytic properties, and strong adsorption capabilities, making them widely applicable in anti-obesity drug delivery. Additionally, some inorganic nanomaterials can work synergistically with phototherapy, significantly enhancing the treatment efficacy for obesity. Organic nanomaterials, including synthetic polymer-based, protein-based, lipid-based, and polysaccharide-based nanomaterials, offer excellent biocompatibility and in vivo degradability. These materials can efficiently deliver drugs to the target site and enable controlled release, while ensuring high drug loading and encapsulation efficiency. By combining these nanomaterials with the targeted and transdermal drug delivery systems discussed above, it is possible to achieve more effective targeting of both visceral and subcutaneous AT (Fig. 4).
Fig. 4.
The overview of various nanomaterials for obesity treatment, and their integration with novel therapeutic approaches. Abbreviations: PTT: Photothermal Therapy; PDT: Photodynamic Therapy, EIH: Electromagnetic Induction Heating, SDT: Sonodynamic Therapy, CNT: Carbon Nanotube.
4.1. Metal-based nanometerials
In recent years, the gradual incorporation of novel therapeutic approaches such as photodynamic therapy (PDT) [98], photothermal therapy (PTT) [99,100], electromagnetic induction heating (EIH) [101] and sonodynamic therapy (SDT) [102] into obesity treatment has led to the broader application of metal NPs. For example, in PTT, the application of near-infrared light at specific wavelengths to the targeted area activates photosensitizers within AT, inducing significant heat production that facilitates the ablation and conversion of white adipocytes [103]. Metals such as Au, Ag, Pd, Pt, and Cu, along with their compounds [104], have been explored as photosensitizers in anti-obesity therapies using PTT. Chen's team selected CuS NPs, which exhibit high photothermal conversion efficiency and excellent biocompatibility, as the photosensitizer for PTT [99]. These NPs were crosslinked with HA and Pluronic F127 through hydrophobic interactions to form CuS hydrogel. When this hydrogel was directly injected into the inguinal region of HFD induced obese mice and subjected to mild PTT, it effectively inhibited further obesity progression and demonstrated systemic weight loss effects, including a substantial reduction in both visceral and subcutaneous AT.
Furthermore, a range of metal nanomaterials can exhibit enzyme-like properties, mimicking the catalytic activities of enzymes such as peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) [[105], [106], [107], [108]]. Single-atom metal NPs, like Au, Pt, Ag, and Pd [109], as well as metal oxide NPs, like CeO2 and MnO2 [110], have demonstrated analogous catalytic activities. Owing to their remarkable ability to scavenge ROS, these nanomaterials have found broad applications in the treatment of obesity and its associated complications. In recent studies, Ding et al. [111] fabricated atomically precise Au22(SG)18 nanocluster enzymes, which the Au22 nanoclusters exhibit both CAT- and SOD-like activities, capable of converting the cytotoxic •O2− into harmless O2, thereby efficiently scavenging ROS in AT. The tripeptide glutathione (SG) can ensure biocompatibility and antioxidant properties, enhance the ROS-scavenging ability. This study demonstrated that Au22(SG)18 nanocluster enzymes significantly alleviated oxidative stress in AT. In HFD induced obese mouse models, treatment with the nanocluster enzyme resulted in a 13% reduction in average body weight, a 47% decrease in iWAT weight, and improvements in glucose tolerance and lipid metabolism dysregulation.
4.2. Nonmetal-based nanomaterials
Nonmetal nanomaterials can be divided into silicon-based and carbon-based subtypes. Silicon-based nanomaterials, such as SiO2 NPs and montmorillonite NPs, have unique porous structures that can adsorb lipases and lipids during the GI digestion process [112,113]. Additionally, the tunable pore sizes and particle shapes make them highly suitable as nanocarriers for anti-obesity drugs. Li's team developed “embedded” structured dual-mesoporous silica nanospheres (EDMSNs), which consist of large mesopores (>10 nm) and small mesopores (2-3 nm) [114]. Subsequently, they loaded the GLP-1R agonist Liraglutide into the small mesopores of the aminated EDMSNs (N-EDMSNs), and the plasmid pFGF-21, which regulates glucose and lipid metabolism and insulin resistance, into the large mesopores. This approach enabled the simultaneous delivery of both anti-obesity genes and drugs (Fig. 5) [115]. In a recently published study, Arooma Jannat et al. successfully applied novel biodegradable periodic mesoporous organosilica (BPMO) NPs for the controlled mitochondrial release of the anti-obesity drug Bezafibrate [116]. BPMO NPs incorporated sensitive chemical linkages like disulfide and tetrasulfide bonds into the mesoporous SiO2 NPs, allowing NPs to degrade in reductive mitochondrial environment and release the encapsulated drug. Under the mediation of BPMO, Bezafibrate significantly enhanced mitochondrial metabolism in adipocytes, reduced intracellular ROS levels, and promoted lipids consumption.
Fig. 5.
Inorganic dual-mesoporous silica nanospheres can be used for the co-delivery of GLP-1 analogs and FGF-21 genes. a. Schematic diagram of the synthesis of EDMSN [114]. Copyright © 2017, Published by American Chemical Society. b. TEM images of EDMSN and N-EDMSNs. c. FGF-21 mRNA and protein levels in the livers of C57BL/6J mice injected with N-EDMSNs/pFGF21 at different quantities. d. Effects of N-EDMSNs/pFGF21-Lira on fasting and glucose tolerance test (GTT) blood glucose levels in HFD-fed C57BL6/J mice [115]. Copyright © 2021, Published by Elsevier Ltd.
Carbon-based nanomaterials, including graphene, carbon nanotubes (CNTs), and carbon nanofibers (CNFs) etc. [117], exhibit the ability to regulate lipid metabolism in adipocytes and achieve weight loss effects [118]. For example, nitrogen-doped carboxylate-functionalized multiwalled carbon nanotubes (N-MWCNTs) have been shown to significantly reduce the size and weight of WAT [119]. Intramuscular injection of N-MWCNTs in mice led to a decrease in the transcription levels of genes related to adipogenesis, and an increase in the transcription levels of genes associated with lipolysis, thus showing promising weight loss effects. Similarly, Sergio de Frutos et al. treated CNFs with purification and depyrogenization process to obtain a novel graphene-like material, GMC [120]. And found that this material could promote lipolysis in adipocytes, and reduce lipid accumulation by increasing the expression of various lipolytic proteins, such as hormone-sensitive lipase (HSL).
4.3. Synthetic polymer-based nanomaterials
Synthetic polymers are one of the primary nanocarriers for drug delivery, which could enhance drug stability, solubility, targeting ability, and biocompatibility [121,122]. At present, PLGA [123], PEG [77], PEI [124], and dendritic polymer PAMAM [58,125] have been applied in the treatment of obesity and its complications. Poly (lactic-co-glycolic acid) (PLGA) is the most widely used nanocarrier due to its excellent biocompatibility and biodegradability. It can be hydrolyzed in vivo into non-toxic lactic acid and glycolic acid, making it FDA-approved as a pharmaceutical excipient [126]. To further enhance the active targeting ability of PLGA NPs, Juhyeong Hong et al. modified them with oligopeptide AHP, and loaded the NPs with Hemin or cobalt protoporphyrin IX (CoPP) [62]. Targeted delivery of Hemin or CoPP to AT can continuously activate Heme oxygenase-1, promoting the consumption and transformation of white adipocytes, while altering the macrophage phenotype in AT and achieving anti-inflammatory effects. As a result, these NPs demonstrated significant therapeutic effects in mouse models of obesity-related complications, including T2D and MASLD.
4.4. Protein-based nanomaterials
Protein-based nanomaterials exhibit excellent biocompatibility and biodegradability, as they are broken down into non-toxic amino acids within the body, which are then reutilized by the organism. The abundant functional groups on the protein surface ensure a high drug loading capacity, and also allow for further modifications. In addition, some proteins possess inherent targeting abilities. For example, recombinant high-density lipoprotein (rHDL) can be recognized by the SR-BI receptor on adipocyte surfaces [127], enhancing the active targeting potential of nanodrugs. Currently, various protein carriers, including gelatin [128], albumin [59,129], lactalbumin [96], and lipoproteins [127], have been successfully applied in the delivery of anti-obesity drugs, demonstrating excellent therapeutic efficacy.
Li's research team utilized α-lactalbumin (α-lac) to encapsulate the anti-obesity agent capsaicin (Cap) [96], and subsequently dissolved NPs in HA-PVA solution to fabricate dissolving MNs. The results demonstrated that α-lac encapsulation increased the hydrophilicity of Cap, thereby enhancing its bioavailability. The drug-loaded MNs not only directly targeted the inguinal subcutaneous AT of obese mice, but also bypassed the strong irritation typically caused by Cap in the oral and GI tract. Additionally, positively charged proteins, as one of cationic polymers, can also selectively target AT. Zhang et al. utilized cationic albumin NPs (cNPs) as a delivery vehicle for the browning agent Rosi [59], ensuring its targeted delivery to WAT cells to induce the browning, thereby achieving anti-obesity effects. The study revealed that cNPs were primarily internalized by adipocytes through clathrin-mediated or electrostatic adsorption-driven endocytosis. Subsequently, the ethylenediamine groups within the cNPs effectively resisted lysosomal acidification, triggering a proton sponge effect and leading to lysosomal swelling and rupture, thereby ensuring the release of the drug into the cytoplasm.
4.5. Lipid-based nanomaterials
Lipid-based nanomaterials are among the most widely used drug delivery nanomaterials in obesity treatment. These materials exhibit diverse structures and formulations, including liposomes, lipid NPs (LNPs), solid lipid NPs (SLNs), and lipid nanoemulsions [22,130,131]. Lipid-based nanomaterials exhibit the following two advantages: First, many natural compounds with anti-obesity properties, such as Resveratrol, Baicalin and Celastrol, face challenges related to poor aqueous solubility and metabolic instability in vivo. Due to their intrinsic lipophilicity, lipid-based nanomaterials serve as ideal carriers for poorly soluble drugs, markedly enhancing both solubility and bioavailability [132,133]. Second, lipid-based nanomaterials exhibit exceptional control over size and surface properties, enabling precise drug delivery tailored to specific pathological mechanisms or tissue types. This tunability forms the basis for subtype-specific and personalized strategies in the treatment of obesity.
Liposomes are nanometer-sized vesicles with a bilayer lipid structure, capable of encapsulating water-soluble drugs within their hydrophilic core and loading lipophilic drugs in their hydrophobic lipid bilayer. Due to their superior biocompatibility, liposomal formulations such as Doxorubicin liposome and Paclitaxel liposome have been successfully employed in clinical cancer therapies [134,135]. In recent years, liposomes have also shown considerable promise in the delivery of anti-obesity drugs and gene therapies. A study conducted by Wang's team found that the lack of miR-145 in extracellular vesicles derived from preadipocytes is closely linked to the inflammatory microenvironment of AT and the progression of midlife obesity [136]. Therefore, the team developed an AHP-modified liposome designed to mimic the function of extracellular vesicles, enabling targeted delivery of miR-145 to AT macrophages. This delivery system effectively inhibited M1 macrophage polarization and demonstrated a preventive effect against obesity in mice. Importantly, this work provides novel insights into the pathogenesis of midlife obesity, and lays the foundation for age-specific strategies in obesity prevention and treatment.
Xu et al. employed lipid nanocapsules (LNCs) to encapsulate reverse micelles loaded with the GLP-1 analog Exenatide, effectively addressing the challenge of oral administration [137]. Following PEGylation, the nanocarrier system demonstrated significantly enhanced in vivo circulation time and intestinal absorption efficiency, leading to elevated GLP-1 secretion levels. In HFD mice, sustained administration of EXE LNC PEG NPs over 4 weeks resulted in marked improvement in insulin resistance (Fig. 6). This team subsequently optimized the formulation by varying the type and ratio of lipid excipients to prepare EXE LNC NPs with different particle sizes [138]. Their findings revealed that particle size modulates the selective release of several gut hormones, including GLP-1, GIP, and PYY. Specifically, smaller NPs (30 nm) preferentially stimulate GIP secretion from proximal intestinal K cells, whereas larger NPs (200 nm) predominantly enhance GLP-1 and PYY secretion from distal intestinal L cells (Fig. 6). This discovery not only validates the tunability of lipid-based nanomedicines in terms of size and composition, but also presents a novel strategy for hormone-based, personalized approaches in obesity and diabetes treatment.
Fig. 6.
Lipid nanocapsules (LNCs) can be used to encapsulate GLP-1 analog exenatide (EXE) to enable its oral administration, and modulate gut hormone secretion. a. Schematic representation of EXE-loaded RM LNC PEG and RM LNC PEG-PRO. Propionate (PRO) is used as a ligand targeting intestinal endocrine L-cells. b. Blood glucose values and mean AUC were tested 30 min before and 120 min after glucose administration. c. Representative images of the fluorescent nanocapsule (red) distribution in the duodenum, jejunum, ileum and colon in 10-week HFD obese/diabetic mice 1 h after the oral gavage of RM LNC. Scale bar = 50 μm [137]. Copyright © 2020, Published by Elsevier Ltd. d. Plasma total GIP levels were measured from the tail vein after oral administration of water (vehicle), 30- or 200-nm RM LNC (1.62 mg/g lipid dose), and 30-nm RM LNC with a high dose (2.43 mg/g lipid dose). Plasma active GIP, active GLP-1, and PYY levels were measured from the portal vein 65 min after oral gavage [138]. Copyright © 2024, Published by The American Association for the Advancement of Science.
Nanoemulsions are lipid-based liquid delivery systems, which immiscible water and oil phases form nanoscale droplets under the influence of surfactants [139]. These systems are widely employed for the oral delivery of poorly soluble drugs. In a study by Lu et al., [140] it was demonstrated that the activation of X-box binding protein 1 (XBP-1), in conjunction with elevated ROS levels, promoted both the proliferation and hypertrophy of preadipocytes. By combining the XBP-1 inhibitor KIRA6 with the antioxidant α-tocopherol, along with emulsifiers phosphatidylcholine and medium-chain triglycerides, they formulated KT-NE nanoemulsions. This formulation mitigated oxidative stress in preadipocytes and inhibited XBP-1 activation, effectively limiting adipocyte hypertrophy and lipid droplet transfer between adipocytes. This study further revealed that KT-NE nanoemulsions could attenuate obesity progression and the development of MASLD in female C57BL/6 mice. Even though they didn't include a male control group or investigate gender differences in obesity mechanisms in detail, it represents the first effort to incorporate gender as a variable in anti-obesity nanomedicine research, providing preliminary insights for the development of gender-specific precision therapies.
4.6. Polysaccharide-based nanomaterials
Polysaccharides are among the most abundant biopolymers in nature, widely recognized for their excellent biocompatibility, biodegradability, and metabolic stability. These characteristics make them ideal candidates for drug delivery applications [141,142]. Polysaccharide-based nanomaterials, such as chitosan, cellulose, starch, and HA, have found extensive use in anti-obesity therapies. Notably, chitosan is the only positively charged polysaccharide known, making it a common nanocarrier for targeting AT in drug delivery systems [60,143]. Cellulose, the most abundant plant-derived polysaccharide, can be utilized to produce cellulose-based hydrogels that mimic the function of dietary fiber, effectively prolonging satiety and contributing to weight loss [144]. Starch, widely available and cost-effective, has been successfully applied in the delivery of anti-obesity agents like resveratrol, to enhance its GI stability and bioactivity [145]. In comparison, HA exhibits a broader range of functions. It has the ability to selectively target AT, as it can be recognized by the CD44 receptor highly expressed on the surface of adipocyte [146]. Meanwhile, HA plays a critical role in transdermal drug delivery systems for obesity treatment. It can form 3D networks through physical or chemical cross-linking, absorbing water and swelling to create hydrogels [147]. Additionally, HA's exceptional hydrophilicity makes it an ideal matrix for the preparation of dissolving MNs, facilitating precise and controlled drug release.
Polysaccharides themselves also exhibit certain anti-obesity effects. Numerous studies have demonstrated that polysaccharides play a critical role in scavenging free radicals, modulating the activity of key enzymes involved in lipid metabolism, and reshaping gut microbiota [147,148]. For example, low molecular weight chitosan (LCS) has been shown to regulate gut microbiota. Luo et al. combined LCS with selenium which is known for its lipid-lowering properties, to fabricate LCS-Se NPs [149]. And found that LCS-Se NPs enhanced the abundance of beneficial gut bacteria such as Bifidobacterium and Akkermansia, while reducing the prevalence of obesity-associated bacteria such as Anaerotruncus and Lachnoclostridium. This regulatory effect significantly improved intestinal barrier damage induced by HFD in mice and reduced the volume of epididymal AT, demonstrating excellent weight-loss effects.
Despite the exploration of various nanomaterials for obesity treatment, apart from the edible hydrogel Plenity, no other nanomedicines advanced to clinical application. As summarized in Table 2, different types of nanomaterials still encounter many challenges related to safety, large-scale production, and long-term storage. Metal NPs such as Au, Ag, Cu, and Pd have been reported to exhibit varying degrees of cytotoxicity and in vivo toxicity [150]. A study by Liu et al. demonstrated that Ag NPs colloid at a concentration of 2.5 μL/mL inhibited the growth of the human HEK-293 cell line by up to 100%, exhibiting significant cytotoxic effects [151]. Furthermore, cationic nanomaterials, designed for AT targeting, can induce cell membrane rupture due to strong electrostatic interactions, potentially resulting in hemolysis, inflammation, and off-target toxicity, thereby limiting their in vivo safety [152].
Table 2.
Characteristics and clinical translation barriers of different types of nanomaterials in obesity treatment.
| Nanomaterial Type | Characteristics | Clinical Translation Barriers |
|---|---|---|
| Metal-based |
|
|
| Nonmetal-based |
|
|
| Synthetic polymer-based |
|
|
| Protein-based |
|
|
| Lipid-based |
|
|
| Polysaccharide-based |
|
|
From an industrial production standpoint, many nanomaterials face challenges when scaling up from laboratory to industrial production. Key parameters such as particle size distribution, uniformity, and drug loading efficiency often fail to remain consistent, and some naturally derived nanomaterials exhibit batch-to-batch variability [153]. Additionally, proteins and liposomes are highly sensitive to environmental conditions, with slight changes in temperature or pH leading to protein denaturation. Increased temperature can also enhance the fluidity of liposome membranes, causing premature drug leakage. These factors result in relatively short shelf lives for nanodrugs, which often require storage at ultra-low temperatures, significantly increasing the cost of production, storage, and transportation [154].
5. Nanomaterial-based strategies for precision obesity treatment
Based on the previous analysis of the lipid metabolism process, the onset and progression of obesity and its associated complications are driven by the digestion, absorption, distribution, storage, consumption of lipids, as well as alterations in the AT microenvironment. Therefore, precision obesity treatment also can be classified into the following five strategies: 1) reducing lipid intake; 2) interfering lipid absorption; 3) inhibiting lipid storage; 4) enhancing lipid consumption; and 5) alleviating chronic inflammation and oxidative stress within AT (Fig. 7). Recent studies have demonstrated that nanomaterials can effectively implement each of these strategies, resulting in significant weight loss outcomes, which will be discussed in detail in this section.
Fig. 7.
The five targeted strategies for obesity treatment (Created in https://BioRender.com).
5.1. Nanomaterials facilitate the reduction of lipid intake
This strategy focuses on controlling dietary lipid intake at its source. Traditional approaches, such as caloric restriction and appetite-suppressing medications, also aim to reduce lipid intake, but their efficacy is often compromised by hunger induced by dieting and the off-target side effects of pharmacological treatments. However, nanomaterials have showed significant potential in prolonging satiety and suppressing appetite, either as adjunctive therapies or as part of innovative drug delivery systems.
Satiety Prolongation. Dietary fibers are resistant to digestion and absorption in the GI tract, contributing to prolonged satiety, reduced calorie density, and a slower food absorption rate [157]. Similarly, hydrogels, which exhibit high water absorption capacity, are also not digested in the stomach and can serve as food additives to mimic the dietary fibers. Marta Madaghiele et al. developed a cellulose-based superabsorbent hydrogel, CB-SAH [144]. It was composed of CMC as the polymer backbone and citric acid (CA) as the crosslinking agent. Upon oral administration, CB-SAH particles rapidly hydrate in the stomach and mix uniformly with ingested food. The pH of GI tract modulates the hydrogel's volume through dehydration or hydration, ensuring its successful transit to the colon, where it is degraded and excreted (Fig. 8a). This cellulose-based hydrogel is calorie-free and effectively enhances GI motility, delays gastric emptying through a mechanobiological mechanism. In clinical trials, this hydrogel demonstrated significant anti-obesity effects, with 59% of participants in the hydrogel group achieving a ≥5% weight loss, significantly outperforming the 42% in the placebo group [158,159]. Successfully, this hydrogel has now received FDA approval for commercial use (brand name: Plenity).
Fig. 8.
Edible superabsorbent hydrogels for prolonging satiety. a. Schematic representation of CB-SAH mimicking the role of dietary fiber in the human gastrointestinal tract [144]. Copyright 2021, Nature journals. b. Schematic diagram of the double network hydrogel structure design, and its principle for long-term gastric retention [160]. Copyright © 2022, Published by Elsevier Ltd.
To further enhance the gastric retention time of hydrogels and prolong satiety, subsequent research developed a double network hydrogel structure [160]. Polyacrylamide was employed as the first network, which rapidly absorbs water and swells upon contact with gastric fluids to remain in the stomach. Chitosan/sodium alginate served as the second network, compensating for the reduced molecular chain crosslinking density caused by swelling, thus ensuring long-term mechanical stability (Fig. 8b). In rabbit models, this hydrogel was observed to remain in the stomach for up to 16 days before being degraded into fragments and excreted, demonstrating exceptional long-term gastric retention and prolonged satiety. In addition, recent studies have continued to report the application of such edible hydrogels in sustained drug delivery and delayed gastric emptying [161,162].
Appetite Suppression. As previously discussed, commonly used appetite suppressants in clinical practice, such as Lorcaserin and Phentermine, exhibit poor selectivity, leading to a range of cardiovascular and CNS effects. While nanotechnology can improve the targeting efficiency of small molecule drugs, the blood-brain barrier (BBB) remains a significant obstacle for CNS-targeted delivery [163]. Up to now, the only reported nanodrug targeting brain lipid metabolism was presented by Jesús et al. in 2023 [164]. This study targeted Carnitine Palmitoyl-Transferase 1A (CPT1A), with its inhibition in the hypothalamus promoting satiety by preventing fatty acid oxidation. Utilizing a core crosslinked micelle-based approach, researchers successfully encapsulated the CPT1A inhibitor, (±)-C75-CoA, and delivered the drug-loaded micelles directly into the mouse CNS via intracerebroventricular injection, bypassed the challenges of crossing the BBB. Therefore, no anti-obesity nanodrugs capable of crossing the BBB have been reported at present, but recent studies suggest that small extracellular vesicles and exosomes may hold potential for CNS-targeted delivery of anti-obesity drugs [165,166].
In addition to direct CNS targeting, modulating the GI tract to delay gastric emptying represents another strategy for appetite suppression. Botulinum neurotoxin A (BTX-A), a potent inhibitor of muscle contraction, can reduce gastric wall muscle contractions and decelerate gastric emptying when locally administered [167,168]. Wang et al. incorporated BTX-A as the active payload and designed a layer-specific gastric paralysis microneedle (LGP-MN) [169]. By precisely controlling the drug-loading position, BTX-A could be selectively injected into the gastric muscular layer, submucosal layer, and mucosal layer (Fig. 9). The results revealed that injection into the muscular layer achieved the most significant therapeutic effects, including a 16.23% reduction in weight and a 55.20% decrease in gastric emptying rate. However, the direct application of this approach to the stomach wall presents challenges for broader clinical adoption, underscoring the necessity for further exploration of noninvasive or implantable methods for gastric paralysis control.
Fig. 9.
LGP-MNs for reducing gastric wall muscle contractions to suppress appetite. a. The dissolving LGP-MNs deliver BTX-A into the gastric wall, exhibiting weight loss and metabolism-improving effects. b. The LGP-MNs use the two-step casting technique to fabricate the soft-substrate dissolving MN patch with refined drug-loaded tips. c. The LGP-MNs are designed with a series of heights, separately targeting the muscular (300 μm), submucosal (600 μm), and mucosal (1000 μm) layers. d. Upon MN dissolution, BTX-A distributes across the designated gastric wall layers and elicits its anticholinergic effect, inhibiting muscle contraction and gland secretion [169]. Copyright © 2023, Published by Wiley.
5.2. Nanomaterials facilitate the interference with lipid absorption
This strategy primarily targets dietary lipids that have been ingested into the GI tract but have yet to be absorbed by the intestinal epithelial cells. The digestion and absorption efficiency of these lipids can be reduced via two pathways. Firstly, by inhibiting GI lipases, which interferes with the hydrolysis and absorption of triglycerides. Secondly, by restoring the diversity of the gut microbiome, its diversity can influence energy absorption and contribute to obesity through multiple ways.
Inhibition of Lipase Activity. Pancreatic lipase is a pivotal enzyme in the hydrolysis and absorption of lipids, catalyzing the breakdown of 50%-70% of dietary lipids [170]. Orlistat is the only FDA-approved pancreatic lipase inhibitor for obesity treatment, but it also leads to a substantial amount of unabsorbed fat in the GI tract, which is associated with many adverse effects like fecal incontinence and oily stools [171]. To minimize these side effects, Li et al. co-administered Orlistat with pine pollen sporopollenin (PPS) microcapsules, which is a core-shell structure extracted from pine pollen [172]. The highly porous and lipophilic properties of PPS significantly enhanced its oil absorption capacity, alleviating the oily stool side effects associated with Orlistat, while also enhancing the drug's weight loss efficacy.
Additionally, nanomaterials such as mesoporous silica particles (MSP), montmorillonite (MMT) and cellulose have shown efficacy in adsorbing or encapsulating GI lipases [173]. A study by Erik R. Waara et al. demonstrated that MSPs with pore sizes ranging from 8.0 to 11.8 nm can encapsulate pancreatic lipase and α-amylase [112], thereby obstructing the absorption of dietary lipids and carbohydrates (Fig. 10). This material is currently undergoing clinical trials (NCT03823027) and has been shown to effectively lower blood glucose and plasma LDL cholesterol levels in participants [113]. Tahnee J. Dening et al. also identified that spray dried MMT particles interfere with lipid absorption by adsorbing significant amounts of medium chain triglycerides and lipolytic products, resulting in a notable reduction in body weight gain in rodent models [174].
Fig. 10.
Engineered mesoporous silica particles (MSP) can entrap digestive enzymes and interference energy absorption. (a) Schematic diagram of engineered MSP adsorbing lipase and α-amylase. (b) Engineered MSP lower α-amylase activity in a pore-size dependent manner in vitro. (c-d) Glycated hemoglobin (HbA1C) and low-density lipoprotein (LDL) cholesterol levels in blood samples from ten subjects with obesity after oral treatment with MSP [112]. Copyright © 2020, Published by Wiley.
Regulation of Gut Microbiota. Obesity is strongly associated with disturbances in gut microbiota diversity. Related studies have found that in obese populations, there is an increase in the relative abundance of Firmicutes and a decrease in Bacteroidetes [175,176]. Furthermore, germ-free mice colonized with an “obese microbiota” exhibit a significant increase in total body fat compared to those colonized with a “lean microbiota” [177]. According to related reviews, the gut microbiota has been shown to influence obesity through multiple physiological processes, including energy absorption, appetite regulation, lipids storage, and chronic inflammation [178]. Rostyslav Bubnov et al. also found that: In the gut microbiota of HFD fed mice, a marked reduction in the abundance of beneficial probiotics, and a significant increase in the population of pathogenic bacteria was observed [179]. However, they also found that the application of CeO2 NPs effectively reversed this trend, and when combined with the probiotic strain L. casei IMV B-7280, the treatment resulted in a marked reduction in serum cholesterol levels. These findings suggest that inorganic NPs like CeO2 and ZnO could act as prebiotics, enhancing the growth of beneficial probiotics [180]. Another study investigated the application of protein hydrogels formed by the self-assembly of flavonoids and amyloid fibrils in obesity treatment [181]. The oral administration of these hybrid hydrogels significantly promoted the proliferation of Parabacteroides, Alistipes, and Bacteroides species in the gut microbiota of HFD fed mice. Meanwhile, fecal microbiota transplants from these mice into germ-free mice resulted in a notable reversal of HFD induced serum cholesterol elevation and obesity, suggesting that the hybrid hydrogel alleviates HFD induced obesity by modulating the gut microbiome.
5.3. Nanomaterials facilitate the inhibition of lipid storage
As the primary tissue for lipid storage, the expansion of WAT is a key contributor to the development of obesity. At its core, the enlargement of WAT results from the hyperplasia and hypertrophy of white adipocytes. Hence, the storage of excess lipids can be suppressed through the following two pathways: inhibiting the increase in adipocyte number (i.e. adipocyte differentiation), or suppressing further hypertrophy of adipocytes.
Inhibition of Adipocyte Differentiation. The formation of adipocytes proceeds through two stages: mesenchymal stem cells (MSCs) differentiate into preadipocytes (commitment stage), and preadipocytes differentiate into mature adipocytes (differentiation stage) [182]. Therefore, inhibition of adipocyte differentiation can be achieved by inhibiting both commitment and differentiation. In commitment stage, nanomaterials like cerium oxide, silica [183], iron oxide [184], and gold NPs [183] have shown the ability to suppress MSC adipogenesis, demonstrating promising anti-obesity effects.
During differentiation stage, conjugated linoleic acid (CLA) is recognized for its ability to inhibit adipocyte differentiation; however, its poor cellular targeting and susceptibility to oxidation pose significant limitations to its in vivo anti-obesity application [185,186]. In order to solve this problem, Xu et al. designed α-tocopherol incorporated Nanostructured Lipid Carriers (tocol NLCs) for encapsulating CLA [132]. The incorporation of α-tocopherol not only prevents the oxidation of CLA, but also enhances the stability and drug loading capacity of the NLCs. The results demonstrated that, compared to free CLA, the delivery efficiency of tocol NLCs was increased by 5.5-fold. In 3T3-L1 preadipocytes, treatment with these NPs significantly suppressed the expression of key transcription factors in differentiation stage, like PPARγ and C/EBPα, thereby obstructing adipocyte differentiation and effectively controlling obesity in HFD induced rats.
Inhibition of Adipocyte Hypertrophy. Adipocyte hypertrophy is primarily driven by the aggregation of lipid droplets within the cells. As previously discussed, both N-MWCNTs and P-G3 NPs have been shown to effectively suppress lipid accumulation. In addition, combining nanomaterials with phototherapy could enable targeted photo-lipolysis of AT. Li et al. developed AIE luminogens (AIEgens), TTMN and MeTTMN, as photosensitizers to combine lipid droplet imaging with PDT [61]. The highly lipophilic TTMN and MeTTMN selectively interact with triglycerides and fatty acids in lipid droplets, enabling specific imaging of WAT. Upon exposure to red/near-infrared light, these AIEgens act as photosensitizers, triggering lipid peroxidation and adipocyte apoptosis. In vivo PDT experiments conducted on BALB/c mice demonstrated that these AIEgens could reduce lipid droplet size and decrease the weight of WAT, effectively controlling body weight and waist circumference.
Luo et al. integrated positively charged stearic-acid-modified chitosan oligosaccharide (COA) with indocyanine green (ICG), a photosensitizer used in PTT, to fabricate COA + ICG@Effervescent MNs [60]. The effervescent MNs, utilizing NaHCO3 as an effervescent agent, generate CO2 upon contact with body fluids, thereby accelerating the separation of MNs from the patches and enhancing their permeability (Fig. 11). This study found that COA NPs alone could inhibit lipid droplet formation in 3T3-L1 adipocytes via autophagy-mediated degradation. When combined with PTT-induced browning and apoptosis, the approach significantly enhanced the depletion of WAT and facilitated weight loss in obese mice, which means the COA@MN group exhibited a 19.66% weight reduction, while the COA + ICG@MN + Laser group exhibited a 37.99% reduction.
Fig. 11.
Schematic illustration of the design and application of effervescent microneedles, as well as their mechanism of action in inhibiting lipid droplet formation and promoting adipocyte browning. [60] Copyright © 2025, Published by American Chemical Society.
5.4. Nanomaterials facilitate the enhancement of lipid consumption
Although both strategies target AT, Strategy 4 aims to deplete adipocytes that have already stored significant amounts of lipids, it is different from Strategy 3 which focuses on inhibiting lipid storage within adipocytes. Compared to creating a caloric deficit to burn fat, utilizing chemical agents or nanomaterials to promote the transformation and consumption of adipocytes might be a more effective approach. Here, we categorize this strategy into two methods: inducing adipocytes browning and targeted adipocytes destruction.
Induction of WAT Browning. AT is primarily divided into two types: white AT (WAT), which stores lipids, and brown AT (BAT), which generates heat by converting lipids into energy. BAT is characterized by its high mitochondrial content and the expression of uncoupling protein 1 (UCP-1), this protein could uncouple oxidative phosphorylation to produce heat [187,188]. While BAT accounts for a small proportion in adult humans, recent studies have found beige adipocytes in adult AT, also express UCP-1 and exhibit thermogenic properties [189]. Several agents, including Rosiglitazone, Baicalin, Resveratrol, can induce the conversion of white adipocytes to beige adipocytes, a process known as “browning”. And nanomaterials have shown promise in improving the targeted delivery, solubility, and synergistic effects of these browning agents (Table 3) [190,191].
Table 3.
The application of nanomaterials in browning agent delivery.
| Browning agent | Limitations | Nanocarrier | Application | Reference |
|---|---|---|---|---|
| Rosiglitazone (Rosi) | Monotherapy exhibits insufficient therapeutic efficacy. | rHDL@RM/MS | Utilizing rHDL as a carrier for the combined delivery of Rosi and Metformin. | [127] |
| HORN MN | HOA NPs, self-assembled from anti-inflammatory oleanolic acid (OA), encapsulate Rosi into MNs for transdermal delivery of both agents. | [194] | ||
| Rosi-cNPs@gel | Cationic albumin NPs (cNP)-mediated delivery of Rosi combined with the thermosensitive agent IR780 in a hydrogel enables synergistic PTT and browning induction. | [59] | ||
| 2,4-dinitrophenol (DNP) | Severe cardiovascular toxicity | TADNP MN | Modifying DNP with tetradecanoic acid (TA) enhances AT targeting, and combined with MN technology to improves localized drug delivery. | [97] |
| Resveratrol (RSV) | Lability, poor water solubility, short biological half-life, and poor systemic bioavailability | RSV-NLC MN | RSV was encapsulated in NLC and loaded into PVA MN patch for transdermal delivery. | [133] |
| RSV@NC@Apt8 | Mesoporous silica-coated gold nanorods (NCs) serve as a carrier, encapsulating RSV within the silica layer. Furthermore, surface modification with PEG and the aptamer Adipo-8 enhances the nanomaterial's biocompatibility and WAT targeting. The gold nanorods integrate localized PTT with the induction of browning. | [195] | ||
| Baicalin (Baic) | Lability, poor water solubility, short biological half-life, and poor systemic bioavailability | Pep-PPIX-Baic NPs | The combination of adipose homing peptide AHP, photosensitizer PPIX, and browning agent Baic enables dual therapy of browning induction and localized PDT. | [63] |
| bcaND | Baic, aptamer Adipo-8, pyrophosphate, and Mg2+ self-assemble via a one-pot method into Baic-compressed aptamer nanodrug (bcaND). | [196] | ||
| Capsaicin (Cap) | Strong hydrophobicity, low bioavailability, high irritancy to the oral and GI tract. | M(Cap) MN | α-Lactalbumin and Cap self-assemble into M(Cap) micelles through hydrophobic interactions. Loading them into MN patch to overcome the poor water solubility. | [96] |
| CSC MN | A micellar solution was prepared by mixing clove oil, sodium caseinate, PEG 400, and Cap in specific proportions, which was then fabricated into MNs. | [197] |
Rosiglitazone (Rosi) is the most extensively employed browning agent, but its monotherapy is still insufficient for effectively treating obesity [192,193]. Recent research has focused on enhancing its effectiveness through combination therapies and targeted delivery strategies. Chen et al. engineered the rHDL@RM/MS nanoplatform (Fig. 12) [127], designed to co-deliver Rosi and the anti-adipogenic agent metformin. In this system, rHDL serves as a carrier that selectively targets the SR-BI receptor on adipocyte surfaces, while pH-responsive sodium alginate-chitosan complex microspheres (MS) facilitate the controlled release of rHDL@RM under intestinal pH conditions. The co-administration of Rosi and metformin resulted in the upregulation of PPARγ expression in 3T3-L1 adipocytes, an increase in mitochondrial biogenesis, and enhanced cellular oxygen consumption, effectively inducing the conversion of white adipocytes into beige adipocytes. Oral administration of this delivery system in HFD induced obese mice led to a remarkable 44.6% reduction in body weight.
Fig. 12.
Schematic illustration of the adipose tissue targeted sequential delivery system regulating glycolipid metabolism for systemic obesity and its comorbidities. [127] Copyright © 2024, Published by Elsevier Ltd.
Baicalin (Baic), a flavonoid extracted from Scutellaria baicalensis, has emerged as an effective agent for inducing adipocyte browning [[198], [199], [200]]. By activating mitochondrial carnitine palmitoyltransferase, Baic could promote fatty acid metabolism, thereby facilitating the transformation of white adipocytes into beige adipocytes. In a study by Ma et al. [63], Baic was combined with the photosensitizer protoporphyrin IX (PPIX) and the oligopeptide AHP. These components were self-assembled into Pep-PPIX-Baic hybrid NPs through Fe3+-induced coordination driven processes. This system was employed to synergistically target WAT for browning induction and PDT. Compared to Baic treatment alone, the dual therapy composed of hybrid NPs and 650 nm laser irradiation, proved significantly more effective in reducing body weight and WAT mass in HFD induced mice. Furthermore, this combined approach led to a marked upregulation of thermogenic genes such as UCP-1 and PGC-1α, also generates cytotoxic singlet oxygen (1O2) that damaged AT. These results underscore the potential of combining PDT with browning induction as a powerful synergistic strategy for anti-obesity.
Targeted WAT Destruction. Even though the browning of WAT represents an innovative strategy for obesity management, its anti-obesity efficacy is not significant. In contrast, directly inducing apoptosis in white adipocytes may be a more effective approach. Various synergistic therapeutic approaches, such as PDT, PTT, and SDT can effectively destroy WAT. Recently, a study innovatively integrated sonosensitizer Zn-TCPP MOF in SDT with CRISPRa-Cas9 technology [102], employing MNs for direct transdermal delivery to the subcutaneous AT. Under the stimulation of ultrasound, Zn-TCPP MOF induces significant ROS production and triggers apoptosis within adipocytes, while the co-delivered CRISPRa-UCP1 plasmid upregulates UCP-1 expression and promotes white adipocyte browning. This combined approach effectively reduced body weight by 18.3% ± 1.7%, improved insulin sensitivity, and inhibited long-term weight regain, demonstrating the powerful synergy of sono-gene combined treatment.
Jiao et al. proposed an innovative approach by camouflaging adipocytes as apoptotic cells to enhance their phagocytosis by macrophages (Fig. 13) [201]. To be specific, this study exploits the apoptotic camouflage property of phosphatidylserine (PS) [202] and adipose-targeting peptide AHP to modify liposomes encapsulating gold nanobipyramids (Au BP), assembling them into PAAu BPs. The sharp edges of Au BP result in a low contact area with the cell membrane, preventing endocytosis and promoting anchoring on the adipocyte surface. This facilitates the exposure of PS to macrophages, thereby enhancing the recognition and phagocytosis of adipocytes. During the clearance, macrophages shift from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, improving the inflammatory environment of AT. Furthermore, the excellent photothermal properties of Au BP enable lipolysis under near-infrared laser irradiation. Overall, the PAAu BPs integrate the functionalities of apoptotic camouflage, anti-inflammatory effects, and PTT together, demonstrating remarkable weight loss effects in obese mouse models.
Fig. 13.
PAAu BPs selectively eliminate adipocytes by inducing apoptosis, diminishing inflammation and PTT. a. PS externalization during the cell apoptosis facilitates the recruitment of macrophages to clear the apoptotic cells by a trogocytosis process. b. Preparation of PAAu BPs by encapsulation of Au BPs with PS- and AHP-modified liposomes. c. Clearance of adipocytes regulated by PAAu BPs that camouflage adipocytes with apoptotic feature through extracellular embedment [201]. Copyright © 2022, Published by Wiley.
5.5. Nanomaterials facilitate the alleviation of chronic inflammation and oxidative stress
AT in obese individuals is often accompanied by the following characteristics: 1) infiltration of pro-inflammatory M1 macrophages; 2) dysregulated secretion of adipokines and inflammatory factors; 3) increased production of ROS and exacerbated oxidative stress; and 4) insulin resistance. These features not only act as triggers for obesity-related metabolic diseases, but also further contribute to fat accumulation, creating a vicious cycle of “obesity-comorbidities-more obesity.” Therefore, alleviating chronic inflammation and oxidative stress in AT plays a crucial role in preventing and managing obesity and its complications.
Alleviating Inflammation. The M1/M2 macrophage ratio in AT serves as a crucial indicator of chronic inflammation. Therefore, suppressing the polarization of pro-inflammatory M1 macrophage and promoting the polarization of anti-inflammatory M2 macrophages are key strategies for mitigating inflammation [203]. Celastrol (Cela), a pentacyclic triterpene derived from Tripterygium wilfordi, has emerged as a potent multi-functional agent, combining anti-inflammatory, leptin-sensitizing, and appetite-suppressing effects [[204], [205], [206]]. As one of the most promising anti-obesity agents, Cela's high lipophilicity limits its solubility and biocompatibility, leading to significant off-target toxicity in vivo [207]. Therefore, various nano-delivery systems such as liposomes, exosomes, and micelles have been employed to enhance Cela's targeted delivery [208].
Liu et al. introduced a novel approach by employing tetrahedral framework nucleic acids (tFNA) as a delivery carrier for Cela (Fig. 14) [209]. In an obesity mouse model, intraperitoneally injected tFNA-Cela exhibited a gradual and uniform distribution across key regions including the head, body, and limbs within 90 min. This delivery system effectively alleviated AT inflammation and insulin resistance, while significantly lowering leptin levels and enhancing energy expenditure. The high loading capacity and biocompatibility of tFNA not only minimized the toxicity of Cela, but also allowed it to function as a “nano-patroller,” precisely targeting systemic sites such as the hypothalamus and AT, thereby enhancing its anti-inflammatory and leptin-sensitizing effects.
Fig. 14.
tFNA-Cela acts as the nano-patroller to provide systemic inflammation alleviation and obesity control. (a) A schematic diagram of tFNA-Cela synthesis. (b) Bio-distribution of tFNA and tFNA-Cela(t-Cel) by intraperitoneal injection. (c) The expression levels of pro-inflammatory (TNF-α, IL-6) and anti-inflammatory (Arg-1, TGF-β) genes detected by RT-PCR (n = 3). (d) H&E staining for observation of the cellular diameter of epididymal adipocytes [209]. Copyright © 2024, Published by Elsevier B.V.
In addition to tFNA, nanomaterials such as bovine serum albumin (BSA) and chondroitin sulfate have also been used for the in vivo delivery of Cela. Moreover, chemical agents such as Simvastatin, Resveratrol, and Metformin have demonstrated excellent anti-inflammatory effects. We have summarized recent findings in Table 4.
Table 4.
The application of nanomaterials in anti-inflammatory drug delivery.
| Anti-inflammatory drug | Limitations | Nanocarrier | Application | Reference |
|---|---|---|---|---|
| Celastrol (Cela) | Highly lipophilic, low bioavailability, and high off-target toxicity | CS-PBE/Cela | Using hydrophobic phenylborate to modify the main chain of chondroitin sulfate (CS) to obtain amphiphilic CS-PBE. It subsequently self-assembles to form micelles and encapsulates hydrophobic Cela. | [210] |
| MET-CS-PBE@Cela | Hydrophilic metformin and hydrophobic PBE were used to modify CS, enabling self-assembly into micelles for encapsulating Cela. The positively charged metformin exhibits certain AT targeting capability. | [211] | ||
| Cela-BSA | The solubility and cellular uptake of Cela were significantly improved by loading it into bovine serum albumin (BSA) NPs via the high-pressure homogenization method. | [129] | ||
| Cel/AHP-NPs@TMC | PEGylated zein core NPs encapsulate Cela, with AHP-conjugated PEG for targeting and a N-trimethyl chitosan (TMC) coating against GI degradation, enabling oral delivery to WAT. | [143] | ||
| Simvastatin (Sim) | Low water solubility, short half-life, limited distribution, and low oral bioavailability (5%). | Sim-PLGA | The synthetic polymer PLGA was employed to encapsulate Sim, resulting in improved absorption and metabolic characteristics. In vivo PK studies demonstrated that Sim-PLGA NPs achieve sustained release for over 30 days, enabling long-term regulation of body weight. | [123] |
| Resveratrol (RSV) | Lability, poor water solubility, short biological half-life, and poor systemic bioavailability | tFNAs-RSV | The anti-inflammatory tetrahedral framework nucleic acid (tFNA) was employed as a carrier for RSV to enhance its stability and biosafety. | [212] |
| MnO2-RSV MN | Nanozyme MnO2 NPs exhibit antioxidant effects. They are assembled with RSV in a core-shell structure into a dry MN powder for direct transdermal delivery into iWAT. | [213] | ||
| Metformin (Met) | Oral bioavailability is relatively low (50-60%), lacking targeted delivery capabilities. | GOQD-HA-Met | Graphene oxide quantum dots (GOQD) were utilized as carriers for Met, with their surface grafted with HA to achieve targeted drug delivery to AT. | [214] |
Neutralizing ROS. In addition to nanozymes, other nanomaterials can also effectively scavenge ROS, such as dicarboxy fullerenes poly (ethylene glycol) molecules (FP). Bai's research team innovatively utilized FP to fabricate charge reversal FPPD NPs [124]. These particles are composed of negatively charged dimethylmaleic anhydride (DMA), positively charged PEI, PLGA linkers, and FP molecules (Fig. 15). In neutral environments, FPPD particles are negatively charged due to the DMA component, but under acidic conditions (pH < 6.0), like inflammatory or lysosomal environments, the amide bonds between DMA and NPs will break down, resulting in a transition to a positive charge. The positively charged NPs can further target macrophage mitochondria, ameliorating oxidative stress and improving mitochondrial function [215]. Consequently, FPPD was shown to effectively quench excess ROS, reduce macrophage overactivation, and alleviate hepatic steatosis in obese mice. This charge reversal property ensures targeted delivery to macrophages and hepatocyte mitochondria, while also mitigates the aggregation and toxicity issues typically associated with cationic polymers [216], offering a safer strategy for the in vivo application of polycations.
Fig. 15.
Schematic illustration of the charge reversal FPPD preparation and the mechanism diagram of FPPD on scavenging ROS and migrating hepatic steatosis. [124] Copyright © 2025, Published by Elseiver.
In this section, based on the mechanism of lipid metabolism, we proposed five strategies for controlling obesity, including: reducing lipid intake, interfering with lipid absorption, inhibiting lipid storage, enhancing lipid consumption, and improving the microenvironment of AT. It's worth noting that, these strategies are not independent, but rather interact synergistically. Many chemical agents and nanomaterials that induce weight loss can simultaneously impact multiple processes. For instance, browning agents such as Resveratrol not only induce the browning of WAT but also alleviate its inflammation [212,213]. CeO2 NPs can both modulate the gut microbiota to suppress lipid absorption [179], and act as nanozymes to neutralize ROS in AT [217], while also inhibiting adipocyte differentiation in commitment stage [218]. Similar multifunctional effects are observed with other inorganic nanomaterials like Au NPs and SiO2 NPs. Furthermore, the combination of various strategies can significantly enhance anti-obesity effect. For example, co-delivery of browning agents with photosensitizers or sonosensitizers to WAT can combine browning induction with PDT, PTT, or SDT, thereby amplifying the overall weight loss effect [98,99,102]. This suggests that synergistic or multifunctional anti-obesity therapies will be a key focus in future obesity research.
Moreover, it is very crucial to integrate their potential adverse effects into account when implementing these strategies (Table 5). For example, inhibiting the growth of AT can lead to quick weight loss, but if this continues for a long time, the AT may shrink, leading to the redistribution of lipid to other organs, which will trigger insulin resistance and associated metabolic disorders subsequently [191]. In addition, while DCA is effective in inducing adipocyte destruction, it is also linked to inflammation and cellular necrosis as side effects [26]. Similarly, cryolipolysis promotes the browning and apoptosis of adipocytes through localized cooling. But clinical studies have shown that this method can trigger some adverse effects, such as paradoxical adipose hyperplasia and AT fibrosis [28]. Even though the specific mechanisms underlying these side effects remain unclear, these phenomena underscore the importance of considering the potential hazards of both AT disruption and browning processes.
Table 5.
Strategies for the application of nanomaterials in obesity treatment and a comparison of advantages and disadvantages.
| Treatment strategy | Measures | Representative nanomedicine/technology | Advantages | Disadvantages |
|---|---|---|---|---|
| Reduce lipid intake | Satiety prolongation | Edible hydrogel Plenity |
|
|
| Appetite suppression | Intragastric satiety-inducing device [219,220] Layer-specific gastric paralysis microneedle (LGP-MN). |
|||
| Interfere with lipid absorption | Inhibit the activity of pancreatic lipase | Mesoporous SiO2 NPs | ||
| Regulate gut microbiota homeostasis | Multiple metal or polysaccharide NPs | |||
| Inhibit lipid storage | Inhibit adipocyte differentiation | Tocol NLC-CLA NPs |
|
|
| Inhibit adipocyte hypertrophy | KT-NE Nanoemulsions Photo-lipolysis technology targeting AT |
|||
| Enhance lipid consumption | Induce the browning of white adipocytes | Cryolipolysis technology WAT-targeted browning agent delivery |
|
|
| Targeted destruction of white adipocytes | Local DCA injection WAT-targeted PDT/PTT/SDT |
|||
| Improve the microenvironment of AT | Alleviate chronic inflammation | WAT-targeted anti-inflammatory agent delivery |
|
|
| Alleviate oxidative stress | Various metal-based nanozymes |
6. Conclusion and prospect
In recent years, global obesity rates have been on a steady rise, making the prevention and treatment of obesity and its associated complications a critical research focus in pharmaceutical development. However, existing therapeutic approaches for obesity are often accompanied by side effects and may not be suitable for patients with mild to moderate obesity. Moreover, the onset and progression of obesity are influenced by factors such as age, gender, and genetics. Against this background, advancing precision obesity treatment strategies has become an essential direction for future research. Nanotechnology, with its superior targeting ability, biocompatibility, and metabolic stability in vivo, has found increasing application in the targeted delivery of anti-obesity drugs. This article systematically proposes five targeted therapeutic strategies based on the overall physiological processes of lipid intake and consumption. The integration of nanomaterials in novel drug delivery systems, such as targeted delivery and transdermal delivery, provides critical technological support for the implementation of these strategies. Additionally, we classified nanomaterials according to their composition, and compare the advantages and limitations of various materials in obesity treatment. Finally, we discuss the specific applications of nanomaterials within targeted obesity treatment strategies and provide a comprehensive analysis of the pros and cons of each approach.
Nevertheless, it should be noted that nanomedicines in the clinical treatment of obesity are still in the early stages. Most research remains at the animal experimentation level, with very few nanodrugs having successfully made it to commercialization. In addition to the challenges previously mentioned, such as large-scale production, long-term storage, and in vivo safety, the strict clinical approval standards also pose a significant barrier. Unlike malignant diseases like cancer, obesity is a chronic condition with long-term, gradual, and non-lethal effects on health, which necessitates stricter safety requirements for treatment approaches [221]. This reality drives the need for more innovative therapeutic strategies, with the clinical advancements of gastric retention hydrogel Plenity [222] and engineered mesoporous SiO2 NPs, “SiPore15” [113], serving as strong examples of this trend. At the same time, research into the specific pathogenic mechanisms of obesity still requires further refinement. While recent studies have unveiled associations between midlife obesity and preadipocytes [136,223], research on key physiological processes such as adipocyte differentiation, maturation, and browning remains inadequate. This limitation results in a scarcity of clear molecular targets for intervention, making precise treatment difficult to achieve. Furthermore, there is still a lack of robust methods for analyzing the in vivo mechanisms and metabolic pathways of nanodrugs, further hindering their clinical translation.
In future research, the improvement of novel drug delivery systems such as transdermal and targeted delivery, as well as the development of weight loss strategies for sub-obese populations, will become key areas of focus. Recently, nanotechnologies such as MNs and hydrogels have been widely explored for the transdermal delivery [74,90], offering potential solutions for self-managed weight control. However, enhancing drug permeation efficiency and expanding the range of applicable conditions remain primary challenges for the continued development. Regarding targeted drug delivery, given the close association between visceral lipid accumulation and obesity-related complications, selective targeting of visceral AT holds promise for achieving superior therapeutic outcomes. Although current studies suggest that cationic polymers possess visceral AT targeting ability [58,59], the in vivo safety still requires further optimization. Meanwhile, for the sub-obese population that has not yet met the clinical diagnostic criteria for obesity but is at potential risk [224,225], developing personalized, safe, and effective obesity prevention strategies will be also be a key direction in nanomedicine research. Overall, future studies must focus on enhancing the precision, safety, and applicability of nanodrugs, further expanding their use in different obesity subtypes and high-risk populations. This will help drive the shift toward personalized and more efficient approaches for obesity prevention and treatment.
CRediT authorship contribution statement
Shanshan Zhang: Writing – original draft, Investigation, Conceptualization. Rangrang Fan: Methodology, Formal analysis. Haifeng Chen: Investigation, Formal analysis. Hanlin Gong: Supervision. Min Mu: Visualization. Bo Han: Writing – review & editing, Project administration. Gang Guo: Writing – review & editing, Funding acquisition, Conceptualization.
Ethics approval and consent to participate
Not applicable. This article is a review and does not involve any studies with human participants or animals performed by the authors.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was financially supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project of China (2024ZD0527200/2024ZD0527205), National Natural Science Foundation of China (82574693, 31971308), National S&T Major Project (2019ZX09301-147), Sichuan Science and Technology Program (2022YFS0007) and Luzhou Science and Technology Plan (2018CDLZ-10). We acknowledged BioRender.com for the support of illustration design.
Footnotes
Peer review under the responsibility of editorial board of Bioactive Materials.
Contributor Information
Hanlin Gong, Email: gonghanlin@scu.edu.cn.
Bo Han, Email: hanbo@shzu.edu.cn.
Gang Guo, Email: guogang@scu.edu.cn.
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