Adipose tissue-targeted drug delivery for treating obesity: current opportunities and challenges

Abstract

Obesity has emerged as a global public health crisis in the 21st century, with its prevalence continuing to rise worldwide. Beyond its well-established links to metabolic diseases (diabetes, hypertension, dyslipidemia, and cardiovascular disease), obesity correlates significantly with oncological and musculoskeletal morbidity. Researchers have discovered that converting energy-storing white adipose tissue (WAT) into energy-expending thermogenic fat through external stimuli or browning agents—a process termed ‘white fat browning’—has become a novel therapeutic strategy for obesity and its complications. This transformation is mediated by the activation of key factors such as uncoupling protein 1 (UCP1), which promotes thermogenesis and energy expenditure in adipocytes, thereby reducing fat accumulation. Studies have shown that certain pharmacological agents (e.g. β3-adrenergic receptor agonists) or natural compounds (e.g. resveratrol, capsaicin) can effectively induce white fat browning. However, systemic administration of these agents may cause off-target effects, such as cardiovascular overstimulation or metabolic disturbances, significantly limiting their clinical application. To address this challenge, adipose tissue-targeted drug delivery systems have been developed. These systems utilize either the unique microenvironment of adipose tissue (e.g. specific receptor expression) or nanocarrier technologies (e.g. polymeric nanoparticles) to precisely deliver browning agents to target fat depots. This review summarizes recent advances in targeted delivery vectors for obesity treatment via white fat browning, while also discussing challenges in nanomaterial design, targeting strategy optimization, and clinical translation.

1. Introduction

Overweight and obesity have been recognized as major risk factors for a wide range of diseases, including cardiovascular diseases, diabetes, cancer, and kidney disorders (Avgerinos et al. 2019; Piché et al. 2020; Artasensi et al. 2023). In recent years, the global prevalence of obesity has risen sharply, particularly in low- and middle-income countries (Blüher 2019). The complications associated with obesity impose substantial economic, social, and healthcare burdens. Currently, clinical management of obesity primarily involves lifestyle interventions (such as caloric restriction and physical activity), pharmacological therapy (including glucagon-like peptide-1 receptor agonists and appetite suppressants), and metabolic surgeries (such as gastric bypass and sleeve gastrectomy) (Rueda-Clausen et al. 2013; Perdomo et al. 2023). However, these approaches suffer from significant limitations: pharmacological therapies are frequently associated with adverse effects, including gastrointestinal symptoms and cardiovascular risks; metabolic surgeries are invasive and costly; while lifestyle interventions are often undermined by poor compliance, making it difficult to achieve sustained weight loss (Rueda-Clausen et al. 2013; Lee SJ and Shin 2017; Perdomo et al. 2023). Consequently, elucidating the precise pathophysiology of obesity and developing targeted, safer therapeutic interventions have become critical priorities in metabolic medicine.

Obesity is primarily caused by an imbalance between energy intake and expenditure, with excess energy stored in adipocytes as triglycerides. WAT, the principal energy reservoir in humans, is mainly distributed in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) (Ibrahim 2010). During fasting or increased energy demand, triglycerides undergo lipolysis to release glycerol and free fatty acids, which are transported via the bloodstream to peripheral tissues for oxidation (Heinonen et al. 2020). Excessive accumulation of WAT, especially VAT, is associated with insulin resistance and chronic low-grade inflammation, contributing to the onset of metabolic syndrome (Karlsson et al. 2019). In contrast, brown adipose tissue (BAT), composed of brown adipocytes characterized by multilocular lipid droplets and abundant mitochondria, is capable of dissipating energy in the form of heat (Scheele and Wolfrum 2020). Recent studies have demonstrated that chronic cold exposure or certain pharmacological stimuli (e.g. β-adrenergic agonists) can induce a distinct population of thermogenic adipocytes known as beige adipocytes (Altınova 2022). These cells express BAT-specific genes such as Uncoupling Protein 1(UCP1) and have been identified in abundance within the inguinal WAT of rodents. Much like brown adipocytes, beige adipocytes are proposed to support the regulation of glucose and lipid levels in the body through their thermogenic function (Yang et al. 2024). Evidence suggests that this ‘browning’ process arises not only from de novo differentiation but also from transdifferentiation of mature white adipocytes (Wang W and Seale 2016; Cheng et al. 2021) (Figure 1). With advances in ^18F-FDG imaging, functional brown fat has also been identified in adults, consisting of both brown and beige adipocytes, and playing a critical role in thermogenesis and energy consumption (Cypess et al. 2009). Notably, the metabolic activity of these adipocytes is inversely correlated with body mass index (BMI) (Cypess et al. 2009). Hence, the conversion of energy-storing white adipocytes into energy-dissipating thermogenic adipocytes represents a promising strategy for the treatment of obesity and its related comorbidities.

Figure 1.

Regulators of white fat browning. Produced with PowerPoint.

Several conventional approaches, including cold exposure, adrenergic stimulation, and exercise, have been validated for their ability to induce WAT browning (Montanari et al. 2017). However, compliance with cold exposure or exercise-based interventions is often poor (Chen KY et al. 2020). By contrast, pharmacological induction of WAT browning is considered a more feasible and efficient alternative (Montanari et al. 2017). Representative browning inducers include β3-adrenergic receptor agonists (e.g. CL316243), peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone (Rosi), Adenosine 5′-monophosphate-activated protein kinase (AMPK) activators like metformin, triiodothyronine (T3), and fibroblast growth factor 21 (FGF21) analogs (López et al. 2010; Ohno et al. 2012; Malin and Kashyap 2014; Cero et al. 2021). In addition, several natural compounds such as Baicalin or celastrol (Cel), have been shown to promote the formation of beige adipocytes, enhance thermogenesis, and ameliorate diet-induced obesity and metabolic syndrome (Qiang et al. 2012; Lee CG et al. 2019; Wang B et al. 2021; Zhang et al. 2022). It is noteworthy that although many of these agents exhibit browning potential, most are administered systemically via oral or injectable routes, which limits their efficacy in localized fat reduction and increases the risk of off-target effects. For instance, CL316243 may affect heart rate and blood pressure (Danysz et al. 2018), whereas Rosi has been linked to increased risk of bone fractures, weight gain, and edema (Ahmadian et al. 2013) (Table 1). The anti-obesity effects of natural compounds are also hindered by their poor aqueous solubility, low oral bioavailability, and rapid metabolic degradation (Wenzel and Somoza 2005; Hou et al. 2020). Consequently, increasing attention has been directed toward developing adipose-targeted drug delivery strategies to enhance therapeutic efficacy, improve bioavailability, and minimize systemic side effects.

Table 1.

Summary of bioactive compounds that induce white fat browning.

Classification	Browning agent	Mechanism	Challenges
β3-AR	CL316243 (Cero et al. 2021)	Activation of β3-sympathomimetic activity	Poor oral bioavailability, poor gastrointestinal absorption, and first-pass hepatic destruction, side-effects (such as increased heart rate and blood pressure)
	Mirabegron (Cero et al. 2021)	Activation of β3-sympathomimetic activity	Cardiovascular side effects
PPARγ agonist	Rosiglitazone (Ohno et al. 2012)	Stabilization of PRDM16 protein	Off-target effects (such as body weight gain, congestive heart failure, bone loss, bone fracture)
AMPK agonist	Metformin (Malin and Kashyap 2014)	Activation of AMPK and FGF21	Low bioavailability, low targeting specificity, gastrointestinal side effects
Notch signaling Inhibitor	DBZ (Bi et al. 2014)	Inhibition of Notch signaling	Off-target effects, large systemic dose requirement, undesired drug accumulation in the liver
TH	T3 (López et al. 2010)	Decreased activity of hypothalamic AMPK, increased SNS activity	Multiple deleterious effects (Cardiotoxicity, bone loss, muscle wasting, perturbation of the neuroendocrine circuit), impair thermogenesis in BAT
BMPs	BMP7 (Boon et al. 2013)	Sympathetic activation	No targeting specificity, systemic side effects
o-3 unsaturated fatty acid	DHA (Zhuang et al. 2019)	Increased mitochondria-mediated β-oxidation	Low enrichment efficiency for adipose tissue, suboptimal bioavailability. easily destroyed by oxidation, low efficacy, unexpected side effects
Nitrogen oxides	NO (Dai et al. 2013)	cGMP-dependent pathways and cross-talk with other molecules such as AMPK, PPARγ, PGC-1α	Low bioavailability
Natural products	Cap (Baskaran et al. 2016), Res (Qiang et al. 2012), et al.	Activation of TRPV1 channels, Sirt1-dependent deacetylation of PPARγ	Considerable hydrophobicity, low bioavailability, obvious irritation of the mouth and gastrointestinal tract

Note: PPAR γ: peroxisome proliferator-activated receptor γ; AMPK: Adenosine 5’-monophosphate-activated protein kinase; T3: triiodothyronine; TH: Thyroid hormone; BMPs: Bone morphogenetic proteins; Bmp7: Bone morphogenetic protein 7; β3-AR: β3-adrenergic receptor; TRPV1: transient receptor potential cation channel subfamily V member 1; SIRT1: NAD-dependent deacetylase sirtuin 1; PGC1-α: peroxisome proliferator-activated receptor-gamma coactivator-1α; BAT: brown adipose tissue; PRDM16: PR domain-containing 16; FGF21: Fibroblast growth factor 21; DBZ: Dibenzazepine; DHA: Docosahexaenoic acid; SNS: Sympathetic nervous system; cGMP: Cyclic guanosine monophosphate; TRPV1: transient receptor potential cation channel subfamily V member 1; Cap, Capsaicin; Res, Resveratrol.

By exploiting molecular recognition (ligand-receptor interactions) or physical targeting strategies, targeted delivery systems precisely concentrate therapeutics at diseased sites while minimizing nonspecific distribution, thereby improving therapeutic indices compared to traditional administration methods (Adepu and Ramakrishna 2021). Moreover, these systems are often designed to provide sustained drug release, maintaining therapeutic concentrations over time and improving clinical outcomes. Current strategies for adipose-targeted delivery in obesity therapy include: the use of vascular-homing peptides to direct drugs to adipose vasculature, magnetic nanoparticles (MNP) guided by external magnetic fields, and microneedle (MN) patches for subcutaneous depot targeting (Xue et al. 2016; Saatchi et al. 2017; Than et al. 2017; Bao et al. 2021; Hiradate et al. 2021; Chen K et al. 2022). Certain inducers, such as Rosi and resveratrol (Res), when modified for targeted delivery, exhibit improved bioavailability, enhanced precision, and reduced toxicity, making them promising candidates for anti-obesity interventions (Chen R et al. 2021; Hiradate et al. 2021; Zu et al. 2021). Given the rapid development of adipose-targeted delivery platforms, there is an urgent need to systematically review existing advancements to inform future research. Accordingly, this review summarizes the construction strategies, surface modification technologies, and therapeutic applications of adipose-targeted delivery systems, while also discussing the current challenges and future directions in the field.

2. Systemic targeted drug delivery systems

2.1. Peptide-modified nanodrug delivery systems

Peptides, composed of amino acids linked by amide bonds, have emerged as essential tools in the field of targeted drug delivery due to their high specificity, small size, ease of modification, and excellent biocompatibility (Ilangala et al. 2021). Notably, their low accumulation in off-target tissues and rapid degradation into amino acids significantly reduce the risk of adverse effects (Li K et al. 2020; Ilangala et al. 2021), offering considerable advantages for their application in obesity therapy. A milestone in adipose-targeting research was the discovery of the PBP (sequence: CKGGRAKDC) in 2004 via phage display technology (Kolonin et al. 2004). This peptide specifically recognizes the PHB receptor on the surface of endothelial cells in WAT, laying a foundation for the development of targeted delivery platforms. Based on this discovery, several studies between 2010 and 2011 successfully constructed PBP-mediated delivery systems (Hossen et al. 2010; Liu et al. 2011). For example, the tPep- vascular endothelial growth factor-B (VEGF-B) fusion protein, developed by Tong’s group, conjugated VEGF-B to the targeting peptide KGGRAKD, enabling preferential targeting of the adipose vasculature and significantly improving metabolic disorders in obese mice (Tong et al. 2020).

With the advancement of nanotechnology, the integration of weight-loss agents and targeting peptides has demonstrated greater therapeutic potential (Table 2). For instance, Chen K et al. (2022) delivered T3 to adipose tissues by encapsulating T3 in liposomes modified with an adipose homing peptide (PLT3), which effectively mitigated systemic side effects while significantly improving obesity-associated metabolic abnormalities. Similarly, To overcome the limitation of Rosi’s off-target effects, Hiradate et al. (2021) developed dual-targeting nanoparticles(NPs) that encapsulate Rosi(Rs-NPs). Their surface was functionalized with two peptides: CKGGRAKDC for adipocyte targeting and the octaarginine (R8) peptide to enhance cellular uptake and regulate intracellular transport. These Rs-NPs induced robust browning responses both in vitro and in vivo and successfully suppressed obesity progression. Compared with single-ligand, dual-targeted formulations elicited higher expression of browning markers without detectable systemic toxicity. Moreover, studies have found that adipose tissue expansion and transformation depend on active angiogenesis, making it a potential therapeutic target for obesity-related disorders. To exploit this, Xue et al. (2016) developed two peptide-functionalized nanoparticle platforms for targeted delivery of either Rosi or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were formed through self-assembly of a biodegradablen poly(lactic-coglycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) triblock polymer conjugated with an endothelial-targeting peptide. The released Rosi induces WAT browning and stimulates angiogenesis, which in turn enhances nanoparticle accumulation in adipose vasculature through a self-amplifying delivery mechanism.

Table 2.

Systemic drug delivery systems.

Classification	Author (year)	Browning agents	Delivery systems	Structure	Administration method	Key findings
Polypeptides	Hiradate et al. (2021)	Rosi	Rs-NP		Subcutaneously injection in inguinal WAT	Efficacy: ↓body weight, fat depots, white adipocytes, the diameter of lipid droplets ↑expression of UCP1 Safety: without any detectable systemic adverse effects
	Xue et al. (2016)	Rosi	PLGA-b-PEG-Peptide/Rosiglitazone NPs		Intravenously injection	Efficacy: ↓body weight, TG, CHO, insulin level ↑expression of UCP1
	Hong and Kim (2022)	HO-1 inducer (hemin and CoPP)	PBP-NPs		Tail vein injection	Efficacy: ↓body weight, glucose level, insulin level, FFA, TG, CHO, LDL ↑HO-1 mRNA levels, Sirtuin-1, expression of UCP1, PGC-1α, PRDM16, HDL
	Chen X et al. (2022)	T3	PLT3		Intraperitoneal injection	Efficacy: ↓body weight, fat mass, adipocyte sizes, TG, FFA, TC, LDL-C ↑expression of UCP1, OCR Safety: devoid of cardiac toxicity and does not cause osteoporosis or impair TSH secretion
	Xian et al. (2023)	Cel	Cel/AHP-NPs@TMC		Oral adminis­tration	Efficacy: ↓body weight, glucose level, TG, CHO, LDL ↑brown fat, expression of UCP1 Safety: reduce the toxicity of Free Cel
	Zu et al. (2021)	Res	L-Rnano		Tail vein injection	Efficacy ↓body weight, % body fat, % body lean, G-WAT, iWAT, adipocyte size, insulin, glucose, leptin, cholesterol, LDL-C ↑expression of UCP1, CD137 Safety: low hepatic toxicity
Aptamers	Chen K et al. (2022)	allicin	DNA-nanoflower-allicin		Intraperitoneal injection	Efficacy: ↓body weight, subcutaneous adipocyte area, TG ↑expression of UCP1, PGC-1α, PRDM16 Safety: No sign of organ or tissue injury indicating the excellent biocompatibility of NFA
	Wang T et al. (2024)	allicin	Aptamer-functiona­lized nano­flower-allicin		Intraperitoneal injection	Efficacy: ↓body weight, lipid accumulation, TC, LDL ↑expression of UCP1, PGC1-α, PRDM16 Safety: No obvious abnormalities or pathological changes in main organs
	Tian et al. (2023)	Baicalin	Baicalin-compressed-aptamer-nanodrug (bcaND)		Intraperitoneal injection	Efficacy: ↓body weight, fat droplet accumulation, TG ↑expression of UCP1 Safety: No significant toxic effect on the liver, kidneys, brain, hematopoietic system, and reproductive system.
	Xu et al. (2023)	DHA	DHA@Apt-NG		–	Efficacy: ↓Triglyceride ↑expression of UCP1, PGC-1α, PRDM16 Safety: low cytotoxicity

Note: Rosi: Rosiglitazone; Cel: celastrol; Res: resveratrol; HO-1: heme oxygenase-1; PBP: Prohibitin binding peptide; NPs: nanoparticles; Rs-NP: Rosi-loaded nanoparticles; PLGA-b-PEG: poly (lactic-coglycolic acid)-b-poly (ethyleneglycol); AHPs: adipose homing peptides; TMC: N-trimethyl chitosan; PBP-NPs: PBP conjugated HO-1 inducer-loaded nanoparticles; T2DM: type 2 diabetes mellitus; NASH: nonalcoholic steatohepatitis; TG: triglyceride; FFA: free fatty acid; UCP1: uncoupling protein-1; PRDM16: PR domain-containing protein 16; PGC-1α: peroxisome proliferator-activated receptor-gamma coactivator-1α; HDL: high-density lipoprotein; CHO: cholesterol; LDL: low-density lipoprotein; PLT3: triiodothyronine(T3)-encapsulated PTP-modified liposomes; OCR: oxygen consumption rate; TSH: thyroid-stimulating hormone; G-WAT: gonadal WAT; iWAT: inguinal WAT; L-Rnano: ligand-coated R-encapsulated nanoparticles; R: Trans-resveratrol; CD137: Cluster of Differentiation 137; FGF21: fibroblast growth factor 21; DHA: Docosahexaenoic acid; Apt-NG: aptamer-functionalized nanogel of gold nanoclusters.

As previously noted, VAT accumulation promotes hepatic lipid deposition, leading to hepatocyte damage and inflammation, both of which are crucial factors in the progression of nonalcoholic fatty liver disease (NAFLD) (Nobarani et al. 2022). Based on this insight, Hong and Kim (2022) developed poly (lactide-co-glycolide) (PLGA)-PBP conjugated NPs loaded with heme oxygenase-1 (HO-1) inducers (hemin and cobalt protoporphyrin IX, CoPP). This Hemin- or CoPP-loaded PLGA NPs (PBP-NPs) not only efficiently induce the differentiation of WAT into BAT in type 2 diabetes mellitus (T2DM) models, but also specifically target PHB-overexpressed fatty liver in nonalcoholic steatohepatitis (NASH), thereby suppressing hepatic uptake of circulating lipids by downregulating lipid storage-related genes (SREBP1c and FASN) expression. Moreover, PBP-NPs demonstrate the capacity to modulate inflammatory macrophage polarization in affected tissues and attenuate systemic inflammation, thereby establishing a novel therapeutic approach for managing obesity, insulin resistance, and concurrent steatohepatitis.

In recent years, novel strategies targeting adipose progenitor cells have attracted increasing attention. Unlike classical BAT, beige adipocytes arise from re-differentiation of adipose-derived stromal cell (ASC) or transdifferentiation of mature white adipocytes. Therefore, promoting ASC-to-beige adipocyte differentiation is considered a promising approach for combating obesity and its complications (Shin et al. 2020). Daquinag et al. (2017) reported that a hypoglycosylated form of decorin (ΔDCN) is selectively exposed on ASC surfaces in both human and murine WAT. Using a cysteine-rich cyclic peptide library, they identified CSWKYWFGEC, a peptide capable of specifically recognizing the ΔDCN receptor, providing a molecular basis for targeted delivery system development. Building on this discovery, Zu et al. (2021) designed a delivery system (L-Rnano) encapsulating Res and modified with a linear ASC-targeting peptide. After intravenous injection, L-Rnano reaches adipose tissue, especially inguinal WAT, via blood circulation. These nanoparticles specifically bind to and are taken up by ASC, and release Res to induce ASC differentiation into beige fat cells, promoting adipose tissue browning and thermogenesis. In contrast, non-targeted Rnano, lacking the targeting peptide, is less efficient in binding to ASC and delivering Res. These results highlight the feasibility of ASC-targeted delivery systems and offer a novel strategy for precise control of adipose progenitor cell differentiation in obesity treatment.

2.2. Aptamer-modified drug delivery systems

Although peptide targeting shows therapeutic potential, aptamer-mediated delivery offers unique advantages in stability and versatility. As DNA or RNA molecules with antibody-like functions, aptamers exhibit exceptional molecular recognition capabilities due to their unique three-dimensional structures. These conformations enable aptamers to bind target proteins with nanomolar to picomolar affinities and high specificity, allowing for precise discrimination between target and non-target cells (Guan and Zhang 2020). Compared to traditional antibodies, these molecules are easily synthesized and chemically modified, and exhibit excellent biostability, low immunogenicity, and rapid tissue penetration, making them highly suitable as ligands for targeted drug delivery applications (Guan and Zhang 2020; He et al. 2020).

Leveraging these advantages, numerous innovative aptamer-based delivery systems have been developed (Table 2). Using cell-SELEX, Liu’s team (Liu et al. 2012) identified an aptamer termed Adipo-8, which binds selectively to mature, differentiated adipocytes while showing no affinity for undifferentiated precursor cells or other cell types. Building upon this, Yu et al. (2020) conjugated Adipo-8 to Polyethylene glycol (PEG)-PLGA NPs to facilitate the delivery of emodin to WAT. The surface modification with Adipo-8 markedly enhanced NPs adhesion to differentiated 3T3-L1 cells and significantly increased intracellular drug accumulation. To address the limited stability of single-stranded aptamers, novel DNA nanoconjugate systems have been developed (Chen X et al. 2022; Wang T et al. 2024). These systems form stable complexes through specific binding between aptamer sequences and a browning agent (Allicin). In detail, a DNA template is prepared and subjected to enzymatic ligation to hybridize 5′ - phosphorylated linear template DNA with primers, forming a circular template. Then, in the optimized reaction system, a rolling circle amplification (RCA) reaction is performed using phi29 DNA polymerase, deoxynucleotide triphosphate, and the circular template DNA at 30 °C for different durations to produce DNA- nanoflowers (NFs). After RCA, free proteins and DNA strands are removed by centrifugation and washing. Allicin is added to the RCA system to create aptamer-functionalized nanoflower-Allicin (NFA). Once inside, NFA releases allicin in the cytoplasm, boosting thermogenic gene expression, especially UCP1, in adipocytes.

In terms of manufacturing, a ‘one-pot assembly’ method was utilized to construct baicalin-aptamer NPs (bcaND) (Tian et al. 2023). The PCR primers are chimed with oxyethylene glycol groups between the Adipo-8 region at the 5′-end and the priming area at the 3′-end. After PCR cycling, the dsDNA amplicons are fused with the single-stranded Adipo-8 domain at the bilateral 5′-ends. During the one-pot controllable assembly procedure, trifunctional baicalin, tri-functional PCR amplicons, pyrophosphate ions, and Mg^{2 +} assemble into an advanced multifunctional nano-vehicle (Figure 2). The electrostatic interaction between the DNA matrix and baicalin allows fine-tuning of particle size from micrometer to nanometer scales. This nano-vehicle demonstrates the ability to target adipose tissue, enhance thermogenesis, and improve assembly efficiency. Compared to conventional DNA self-assembly, this platform offers several advantages, including rapid preparation, simplified processing, and cost-effectiveness. By contrast, based on gold nanoclusters, Xu and colleagues (Xu et al. 2023) developed an aptamer-functionalized nanogel system DHA@Apt-NG, designed for precision delivery of the browning agent docosahexaenoic acid (DHA). This system exhibits several favorable properties, including nanoscale dimensions, strong intrinsic fluorescence, minimal toxicity, and high targeting efficiency toward white adipocytes. In vitro experiments demonstrated that treatment with DHA@Apt-NG significantly upregulated the mRNA expression of key browning genes. However, In vivo evaluation of this system remains to be validated.

Figure 2.

Schematic illustration of one-pot controllable assembly of a baicalin-condensed aptamer nanodrug. Reproduced with permission from Tian et al. (2023). Copyright 2022 WILEY-VCH Verlag GmbH.

2.3. Oral targeted drug delivery systems

As previously discussed, peptide- and aptamer-modified nanocarrier systems enable precise systemic targeting of adipose tissues. However, reliance on intravenous or intraperitoneal administration limits their clinical translatability due to poor patient compliance and high medical costs during long-term treatment. In contrast, oral administration offers noninvasiveness, high patient acceptability, and convenience, making it highly suitable for chronic metabolic disease management and a critical focus in anti-obesity drug delivery research. Notably, oral delivery systems face multiple physiological barriers in drug delivery, which significantly impact the efficacy and bioavailability of drugs. Firstly, gastric acid and digestive enzymes in gastrointestinal tract can lead to drug degradation, thereby reducing their effectiveness (Zhang et al. 2025). Moreover, the tight junctions of intestinal epithelial cells limit drug absorption, especially for large molecules such as proteins and peptides, where this limitation is particularly pronounced (Han R et al. 2024).

Despite the multiple physiological barriers faced by oral delivery systems, these challenges are being overcome through advanced drug delivery technologies and strategies. For instance, Cel, a bioactive compound extracted from the traditional herb Tripterygium wilfordii Hook. F, shows potent anticancer, anti-inflammatory, and anti-obesity properties, but its clinical use is hampered by extremely poor solubility and bioavailability (Hou et al. 2020). To overcome these challenges, Xian’s team (Xian et al. 2023)developed a tri-layer oral nanoparticle system (Cel/AHP-NPs@TMC). In detail, the core of the system is composed of amphiphilic PEGylated zein NPs, which serve to encapsulate Cel. Subsequently, adipose-homing peptides are conjugated to the surface of these NPs, enabling targeting to WAT. Finally, a layer of N-trimethylated chitosan (TMC) is coated onto the adipose homing peptides-modified NPs. The TMC coating is intended to protect the nano-system from degradation in the gastrointestinal environment and to enhance intestinal absorption. This nano-system has been demonstrated to improve the oral bioavailability of Cel, protect it from degradation in the gastrointestinal tract, and facilitate its targeted delivery to the vasculature of WAT, thereby achieving efficient anti-obesity effects. This study provides a valuable technical reference for developing efficient and safe oral targeted delivery systems for obesity therapy.

3. Local injection-based delivery systems

Local injection enables the direct delivery of therapeutic agents to target tissues at effective concentrations without requiring high systemic doses, thereby minimizing off-target side effects (Halwani 2022). This delivery strategy offers unique advantages in the context of obesity treatment, particularly for precise interventions in SAT (Sibuyi et al. 2019). In recent years, nanocarrier systems and hydrogel platforms have been extensively explored to achieve localized and controlled release of Notch signaling modulators, macromolecular agents, and various browning inducers within adipose depots (Table 3). These innovative approaches address the limitations of conventional systemic delivery and provide novel strategies for treating obesity and its associated metabolic dysfunctions.

Table 3.

Localized drug delivery systems.

Classification	Author (year)	Browning agents	Delivery systems	Structure	Administration method	Key findings
Local Injection	Jiang et al. (2022)	DBZ	DBZ-NPs		subcutaneous injection	Efficacy: ↓body weight, inguinal WAT size, blood glucose, cholesterol ↑expression of UCP1, mitochondrial genes Cox5b, Cox7a
	Ren et al. (2022)	NO	PANO gel		subcutaneous injection	Efficacy: ↓body weight, fat mass, adipocyte size, triglyceride, cholesterol, fasting glucose, insulin levels ↑expression of UCP1 Safety: a biocompatible peptide-based material
	Ruan et al. (2023)	Menthol	C@cLip-Gel		subcutaneous injection	Efficacy: ↓body weight gain, white adipocytes sizes, oil droplets, triglycerides, lean mass, fat mass ↑expression of UCP1, carbon dioxide generation, heat production Safety: nontoxic
	Han R et al. (2024)	Res	rHDL@Res/gel		subcutaneous injection	Efficacy: ↓body weight, the ingWAT weight, adipsin, resistin, blood glucose, fatty acids, triglyceride, cholesterol ↑expression of UCP1, PGC-1α, Cidea, C/EBP α, FGF21, PPARγ Safety: mitigate direct drug-induced bodily stimulation and reduce toxicity, excellent biocompatibility and degradability
	Wan et al. (2022)	P-G3	–		intraperitoneal injection	Efficacy: ↓body weight, fat mass, depot sizes ↑heat production, O2 consumption Safety: probably at the sweet spot between efficacy and safety
MN	Zhang et al. (2017)	Rosi/CL 316243	Rosi MN, CL 316243 MN		inguinal skin	Efficacy: ↓body weight, blood glucose, inguinal fat pad, adipocytes in inguinal WAT ↑Adiponectin Safety: exhibited excellent biocompatibility
	Dangol et al. (2017)	Caffeine	caffeine-loaded dissolving microneedle patch (CMP)	–	dorsal skin	Efficacy: ↓body weight, leptin, Triglyceride, total cholesterol, low-density lipoprotein (LDL)-cholesterol ↑adiponectin, HDL-cholesterol
	Than et al. (2017)	CL316243/ T3	CL316243-loaded MN-patch, T3-loaded MN- patch		inguinal skin	Efficacy: ↓body weight, weight of IgWATs, ↑expression of UCP1, PGC-1α, mitochondrial biogenesis marker (COX1)
	Bao et al. (2021)	Cap	MP-M (Cap)		abdominal skin	Efficacy: ↓body weight, body fat, TG, TC, LDL-C ↑expression of UCP1, PGC-1α Safety: The heart, liver, spleen, lung, and kidney and the serum biochemistry values of AST, ALT, LDH, and ALP did not show any abnormalities
MLs	Than et al. (2020)	CL316243/Rosi	CL316243, Rosi-loaded MLs		inguinal skin	Efficacy: ↓body weight, white fat masses (IgWAT and EpiWAT), cholesterol, triglycerides, insulin ↑expression of UCP1, PGC-1α, PRDM16 Safety: minimally invasive and painless, without causing harmful effects on the targeted tissue and body.
INT	An et al. (2020)	Rosi	Rosi-DNs		inguinal skin	Efficacy: ↓body weight, glucose level, iWAT Safety: Little toxicity and adverse effects on the skin tissue
	Abbasi et al. (2022)	Met	MN (met) + INT		inguinal skin	Efficacy: ↓body weight, body fat percentage, iWAT mass, RER ↑expression of UCP1, PGC-1α, PRDM16, pAMPK protein
PDT	Lee MMS et al. (2023)	–	AIEgens (MeTTMN, TTMN)		intravenous injection + abdominal laser irradiation	Efficacy: ↓body weight, waistline, glucose level, iWAT, EpiWAT, fat mass to body weight ratio Safety: had negligible phototoxicity and excellent biocompatibility
	Chen R et al. (2021)	Rosi	Pat-HBc/RSG&ZnPcS4		intravenous injection + abdominal laser irradiation	Efficacy: ↓body weight, body fat, lipid droplets ↑expression of UCP1, Cidea-1, PGC-1α, VEGF Safety: No any detectable cardiac, hepatic or renal damage
	Ma et al. (2024)	Baicalin	Pep-PPIX-Baic NPs		intravenous Injection + abdominal, inguinal and interscapular laser irradiation	Efficacy: ↓body weight, WAT, TC, HDL-C ↑expression of UCP1, PGC-1α, BAT Safety: exhibited the excellent biocom- patibility and no hepatotoxicity
PTT	Lee JH et al. (2017)	–	HA-HAuNS-ATP		abdominal skin + NIR laser irradiation	Efficacy: ↓PA amplitude Safety: no adverse effect on the skin
	Zan et al. (2022)	Mirabegron	CuS-gel		subcutaneous injection + NIR laser irradiation	Efficacy: ↓body weight, iWAT, EpiWAT, adipocyte size, fat mass, cholesterol, triglyceride, insulin, glucose ↑expression of UCP1, PPARγ Safety: exhibited negligible cytotoxicity and biocompatibility.
	Zhang et al. (2024)	Rosi	RSG- cNPs@GEL		subcutaneous injection + NIR laser irradiation	Efficacy: ↓body weight, waist circumference, fat weight, lipid droplets, blood glucose, TC, LDL-C, TG ↑expression of UCP1 Safety: RSG-cNPs@GEL demonstrated minimum in vivo toxicity at the doses under investigation
SDT	Guo et al. (2021)	Bmp7	SmartExo@Bmp7		tail vein injection + ultrasound irradiation	Efficacy: ↓body weight, adipocyte size ↑expression of UCP1, BMP7 protein
Magnetic field induction	Saatchi et al. (2017)	Rosi	Rosi-MNPs		subcutaneous injection	Efficacy: ↑PPARγ target gene expression

Note: DBZ: dibenzazepine; NO: Nitric oxide; Res: Resveratrol; NPs: nanoparticles; HFD: high-fat diet; rHDL@Res/gel: the encapsulation of rHDL@Res within atemperature-sensitive hydrogel; IC@cLip-Gel: nanocontroller-mediated dissolving hydrogel that contained menthol-cyclodextrin inclusion complexes; PANO gel: peptide amphiphiles-NO-releasing nanomatrix gel; P-G3: polyamidoamine generation 3; FGF21: fibroblast growth factor 21; UCP1: Uncoupling protein 1; WAT: White adipose tissue; Cox5b: Cytochrome C Oxidase Subunit 5B; Cox7a: Cytochrome C Oxidase Subunit 7A1; PGC-1α: peroxisome proliferator-activated receptor-gamma coactivator-1α; C/EBP α: CCAAT enhancer binding protein α; PPARγ: peroxisome proliferator-activated receptor γ. MN: microneedle; Rosi: Rosiglitazone; Met: Metformin; IgWAT: inguinal white adipose tissue; MP: microneedle patch; M: nanomicelles; Cap: capsaicin; EpiWAT: epididymal WAT; DNs: drug nanocarriers; INT: iontophoresis; RER: respiration exchange ratio; pAMPK: phosphorylated AMP-activated protein kinase; MLs: micro-lances; PRDM16: PR domain-containing protein 16; iWAT: Inguinal white adipose tissue; TG: Triglyceride; TC: Total Cholesterol; LDL-C: Low Density Lipoprotein; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; LDH: Lactate dehydrogenase; ALP: alkaline phosphatase; COX1: Cyclooxygenase-1; PDT: photodynamic therapy; AIEgens: Aggregation induced emissive luminogens; ZnPcS4: zinc phthalocyanine tetrasulfonate; HBc: Hepatitis B core; VEGF: vascular endothelial growth factor; Pep-PPIX-Baic NPs: adipose-targeting ultra-small hybrid nanoparticles; HDL-C: high-density lipoprotein cholesterol; TG: triglycerides; PTT: Photothermal Therapy; HA-HAuNS-ATP: hyaluronate-hollow gold nanosphere- adipocyte targeting peptide; NIR: near-infrared; PA: photoacoustic; CuS-NDs: Copper sulfide nanodots; CuS-gel: CuS-ND incorporated hydrogel; mPTT-PCT: photothermal-pharmacotherapy; RSG-cNPs: RSG-loaded Cationic bovine serum albumin nanoparticles. SDT: Sonodynamic Therapy; Bmp7: Bone morphogenetic protein 7; Ce6: Chlorin e6; MNP: magnetic nanoparticle.

Studies have demonstrated that inhibiting the Notch signaling pathway can effectively promote the browning of white adipocytes (Bi et al. 2014). However, when administered systemically, pathway inhibitors such as diazepines (DBZ) may cause other off-target side effects (Pajvani et al. 2013; Bi et al. 2014). To overcome these challenges, Jiang et al. (2022). developed PLGA NPs loaded with DBZ, which were directly injected into inguinal WAT. Once taken up by the adipocytes, the NPs release DBZ to locally inhibit Notch signaling over an extended period. This localized strategy successfully induced adipose browning while minimizing systemic side effects. Beyond NPs, dendritic polymers offer another promising approach. Wan’s group developed a polycation-based nanomedicine polyamidoamine generation 3 (P-G3), which exhibited selective accumulation in VAT in murine models (Wan et al. 2022). Unlike traditional agents, P-G3 modulated nutrient-sensing pathways to rebalance lipid metabolism and suppress adipocyte hypertrophy, leading to the formation of smaller, metabolically active ‘miniature’ adipocytes and a reduction in VAT accumulation. Future studies may focus on integrating P-G3 with localized drug delivery systems to enhance tissue specificity and prolong therapeutic efficacy.

In localized injection delivery strategies, hydrogels have emerged as another important platform due to their excellent biocompatibility and controlled release properties. As three-dimensional network polymers mimicking the extracellular matrix, injectable hydrogels are particularly suited for localized drug administration to adipose tissues (Li J and Mooney 2016; Rizzo and Kehr 2021). For example, Ruan’s group developed an injectable hydrogel (IC@cLip-Gel) composed of carboxymethyl chitosan and alginate aldehyde, crosslinked via dynamic Schiff base bonds for the sustained release of menthol (Ruan et al. 2023). Upon subcutaneous injection, the hydrogel absorbs tissue fluid, swells, and expands its mesh structure to release menthol-cyclodextrin inclusion complexes. The released cold-mimetic menthol promotes the transformation of white adipocytes into beige adipocytes, upregulates UCP1 expression and enhances energy expenditure. Similarly, Ren et al. designed a peptide amphiphile– nitric oxide -releasing nanomatrix hydrogel (PANO gel), which facilitated mitochondrial biogenesis and BAT activation via NO release, while also improving cerebral blood flow and cognitive function—a dual benefit for metabolic and neurological health (Ren et al. 2022). Most notably, Han’s group (Han R et al. 2024) constructed a thermosensitive hydrogel incorporating recombinant high-density lipoprotein (rHDL@Res/gel). The rHDL@Res NPs mimic the structure of natural high-density lipoprotein, utilizing ApoA-I mimetic peptides to specifically bind to scavenger receptor B1, which is highly expressed on the surface of adipocytes. Upon local injection, the temperature-sensitive hydrogel undergoes a sol-gel phase transition near body temperature, allowing for the slow release of Res. This prolongs its action time in adipose tissue, upregulating UCP1 expression, inducing adipocyte browning, and ultimately reducing local adipose tissue (Han R et al. 2024). Collectively, these studies demonstrate that hydrogel-based delivery systems enable spatiotemporal control of drug release, offering a safe and effective strategy for obesity treatment.

4. Transdermal delivery systems

In addition to local injection, recent advances in transdermal delivery, especially MN platforms, have shown great promise for targeted delivery of anti-obesity agents to subcutaneous WAT (Hao et al. 2017). These approaches allow for localized drug administration with minimized systemic exposure. Compared to oral administration, transdermal delivery bypasses first-pass hepatic metabolism, reduces systemic clearance, and enhances bioavailability (Kurmi et al. 2017). Such features make transdermal delivery an attractive strategy for novel anti-obesity therapeutics (Table 3).

4.1. MN

Among various transdermal technologies, MN have emerged as a leading modality due to their minimal invasiveness and delivery efficiency. These systems consist of micron-scale projections (typically 10–2,000 µm in height and 10–50 µm in width) arranged on a patch base (Waghule et al. 2019). As a pain-free and user-friendly delivery tool, MN can breach the stratum corneum within minutes to deliver drugs into the dermis. They offer several advantages over traditional routes: ease of administration, improved patient compliance, and effective delivery of biologics, including antibodies and proteins (Luo et al. 2023). Owing to these benefits, MN have gained widespread attention for their clinical potential in targeting localized subcutaneous fat depots.

A representative example is the degradable MN patch developed by Zhang et al. (2017), which embedded drug-loaded NPs into a cross-linked polymer matrix and incorporated them into an MN array. In details, the NPs were prepared by encapsulating browning agents (e.g. Rosi), glucose oxidase, and catalase from pH-sensitive acetal-modified dextran. Subsequently, these NPs were coated with alginate and loaded into the microneedle-array patch made of cross-linked hyaluronic acid matrix. When applied to the skin, the MNs penetrate the skin’s surface, delivering the NPs into the subcutaneous WAT. The glucose oxidase in the NPs reacts with glucose in the physiological environment to generate an acidic microenvironment, triggering the degradation of the dextran NPs and the subsequent release of Rosi, leading to suppressed adipocyte hypertrophy and enhanced metabolic activity. Following this work, Dangol et al. (2017) created a dissolvable MN patch that reduced body weight by 12.8 ± 0.75% in obese mice over six weeks and improved lipid profiles. Than et al. (2017) further developed a detachable polymeric MN patch capable of long-term drug release, thus eliminating the need for daily dosing while promoting WAT browning.

More recently, microlens (ML) systems with core–shell structures have been engineered to co-deliver dual agents, extending the dosing interval to once every two weeks and improving outcomes in metabolic syndrome (Than et al. 2020). In detail, a dry mix of PLGA, drug, and sodium chloride particles was placed on a PDMS mold. After heating, pressing, and cooling to room temperature, PLGA microlens (PLGA-MLs) were obtained. To achieve either biphasic release of a single drug or differential release rates for two drugs, a fast-dissolving biocompatible carboxymethyl cellulose layer was coated onto PLGA-MLs via dip-coating, creating core-shell structured ML. This thermal pressing method features simple operation, short processing time, and low cost, making it suitable for automated mass production. In another innovative study, Bao’s (Bao et al. 2021) team a multifunctional MN patch with capsaicin-loaded micelles (M (Cap)), which were prepared through the self-assembly of α-lactalbumin peptides and capsaicin. These micelles were then incorporated into a hyaluronic acid and polyvinyl alcohol-based MN patch with body temperature-responsive melting properties. Upon penetration into adipose tissue, M (Cap) undergoes cellular endocytosis, subsequently regulating adipocyte lipogenesis and promoting white adipocyte browning.

4.2. Iontophoresis (INT)

Beyond MN, INT (a noninvasive physical enhancement method) has emerged as a promising approach for transdermal drug delivery. By utilizing external energy (e.g. electric current) to temporarily modulate skin barrier function, INT enhances drug permeation while offering distinct advantages including delivery efficiency, excellent compliance, and precise dosing control (Dhote et al. 2012; Andrade et al. 2023). For instance, An et al. (2020) pioneered an iontophoretic delivery system capable of driving charged DNs across the skin barrier. The reverse electrodialysis(RED) battery was operated by the transport of Na⁺ and Cl⁻ ions from concentrated to diluted layers through the cation exchange membranes and anion exchange membranes, respectively. The polypyrrole-incorporated poly (vinyl alcohol) electroconductive hydrogel was fabricated, and the hydrogel patches were constructed with the RED system. Electrically mobile drug nanocarriers were composed of both fluconazole-loaded microemulsion or rosiglitazone-loaded transfersome. The RED-empowered electrical current would flow through the electroconductive hydrogel patches and allow the nanocarriers to penetrate into the skin by repulsive force. Their Rosi-based iontophoretic nanocarrier exhibited potent anti-obesity effects. With the rapid development of MN and nanocarriers, the integration of INT with other transdermal technologies is ushering in a new era of precision delivery. Abbasi’s team combined dissolvable PLGA MN with INT for metformin delivery (Abbasi et al. 2022). Compared to monotherapy, the combined system demonstrated superior anti-obesity efficacy, characterized by slower weight gain, reduced adipose volume, and enhanced thermogenic energy expenditure via WAT browning. These advances highlight INT-based hybrid systems as promising strategies for efficient obesity management.

5. Exogenous stimulation strategies

In recent years, exogenous stimulation strategies have demonstrated tremendous potential in obesity treatment. Photodynamic therapy (PDT) and photothermal therapy (PTT), as representative optical modalities, enable both selective adipose tissue ablation and synergistic browning effects through targeted activation of photosensitizers or photothermal agents. Sonodynamic therapy (SDT) capitalizes on the superior tissue penetration of ultrasound to facilitate precise deep adipose intervention when coupled with sonosensitizers. Complementing these approaches, magnetically targeted therapy employs external magnetic fields to direct superparamagnetic nanoparticles with enhanced therapeutic precision. Notably, through innovative nanocarrier engineering and multimodal combination strategies, these approaches are effectively overcoming the inherent limitations of monotherapeutic modalities (Table 3).

5.1. PDT

Photosensitizers are central to PDT efficacy. When activated by specific light wavelengths, they generate cytotoxic reactive oxygen species that induce cellular damage or apoptosis (Sobhani and Samadani 2021). Lee MMS et al. (2023) developed aggregation-induced emission luminogens (AIEgens), specifically TTMN and MeTTMN, which targeted intracellular lipid droplets and triggered light-induced peroxidation in adipocytes. Despite its rapid and direct response, the clinical application of PDT is limited by the shallow penetration of light, restricting it to superficial fat layers. To address this, a synergistic strategy termed photodynamic- browning has been proposed. For instance, Chen R et al. (2021) developed a WAT-targeting complex (P_at-HBc/RSG&ZnPcS4) incorporating traceable zinc phthalocyanine tetrasulfonate (ZnPcS4) (a photosensitizer) and Rosi. In detail, the adipose-targeting peptide motif (Pat) is incorporated into the major immunodominant region of the hepatitis B core (HBc) protein to construct Pat-HBc virus-like particles (VLPs). These VLPs are then loaded with Rosi and ZnPcS4 through a disassembly–reassembly process. Following intravenous injection, adipocytes treated with Pat-HBc/RSG&ZnPcS4 exhibited significantly enhanced lipolysis under illumination, potentially attributable to the combined effects of Rosi -induced browning and ZnPcS4-mediated photodynamics. Likewise, Ma et al. (2024) engineered hybrid NPs (Pep-PPIX-Baic NPs) consisting of targeting peptides, Fe³⁺, protoporphyrin IX (PPIX, a photosensitizer), and baicalin (a browning agent). Fe³⁺ reacts with PPIX and baicalin in an aqueous solution under ultrasonication to form NPs. The targeting peptide CKGGRAKDC is then added to endow the NPs with the ability to specifically accumulate in WAT (Figure 3). After injecting Pep - PPIX - Baic NPs into obese mice, the NPs gradually accumulate in adipose tissue. Upon laser irradiation, PPIX is activated to generate reactive oxygen species such as ¹O₂, which induces adipocyte apoptosis and reduces fat tissue. Concurrently, baicalin is released from the NPs within the adipose tissue, promoting browning and increasing energy expenditure.

Figure 3.

Schematic illustration of the ultra-small hybrid nanoparticles (Pep-PPIX-Baic NPs) that combine PDT and adipose browning induction for obesity treatment. Reproduced with permission from Ma et al. (2024). Copyright 2024 John Wiley & Sons.

5.2. PTT

Similar to PDT, PTT utilizes photothermal agents to convert near-infrared (NIR) light into heat, leading to local ablation of target cells. As promising photothermal agents, gold NPs have been widely investigated (Wu M et al. 2024). Lee JH et al. (2017) designed HA-HAuNS-ATP, a construct coupling hyaluronic acid hollow gold nanospheres with adipocyte-targeting peptides, which enabled efficient photothermal ablation of subcutaneous WAT under NIR irradiation in obese mice. Furthermore, Zan et al. (2022) developed a hydrogel incorporating CuS-NDs and Mirabegron based on a triple-therapy fat-reduction strategy. Upon NIR light exposure, the hydrogel converts light energy into heat, activating the TRPV1 channel (a thermosensitive pain receptor) and promoting the conversion of WAT into BAT. Meanwhile, Zhang et al. (2024) synthesized cationic albumin nanoparticles (cNPs) loaded with rosiglitazone (Rosi cNPs), which were incorporated into an IR780-containing thermosensitive hydrogel for subcutaneous injection. When exposed to NIR laser irradiation, IR780 generates localized hyperthermia. Simultaneously, the cNPs facilitate targeted delivery of Rosi to white adipocytes, promoting WAT browning and alleviating insulin resistance.

5.3. SDT

As a novel approach, SDT has evolved from PDT that combines low-intensity ultrasound with sonosensitizers. Compared with PDT, SDT displays greater tissue penetration, more concentrated effects at the target lesions, and lower costs (Chen P et al. 2023). Guo et al. (2021) developed an exosome-based delivery platform incorporating a novel conjugate (CP05-TK-mPEG) and the sonosensitizer chlorin e6 (Ce6). To evaluate therapeutic efficacy, Bone morphogenetic protein 7 (Bmp7) mRNA was encapsulated into exosomes, forming SmartExo@Bmp7. Mice are intravenously injected with SmartExo@Bmp7 and then subjected to ultrasound irradiation on the abdominal adipose tissue. The Ce6 generates reactive oxygen species, which break the thioketal bond, enabling the controlled removal of PEG from the exosomes and enhancing endocytosis. This process allows for the efficient delivery of Bmp7 mRNA to the abdominal adipose tissue, promoting the browning of omental adipose tissue, as evidenced by an increased expression of Ucp1. Given Bmp7’s roles in cardiovascular and metabolic regulation, this localized ultrasound-mediated delivery avoided systemic side effects. Furthermore, this system enables the precise targeting and controlled release of browning agents within deeper tissues by utilizing specific sound wavelengths tailored to the target location.

5.4. Magnetically targeted therapy

Building on SDT’s success in deep-tissue targeting, magnetically guided strategies offer complementary advantages. MNP exhibit unique physicochemical properties and have demonstrated great potential in biomedical applications (Nowak-Jary and Machnicka 2023; Rezaei et al. 2024). Recent research has revealed that superparamagnetic iron oxide NPs (SPIONs) can be guided by external magnetic fields (Estelrich et al. 2015). significantly enhancing therapeutic agent accumulation in adipose tissue. Saatchi et al. (2017) developed a Rosi-loaded MNP delivery system that effectively activates the PPARγ signaling pathway. Given Rosi’s hydrophobic properties, it can be efficiently adsorbed onto the hydrophobic coating of MNP. This interaction not only significantly increases drug loading capacity, but also promotes the fusion and internalization of MNP with adipocyte membranes. Following cellular uptake, MNP primarily localize in the cytoplasm, potentially undergoing degradation or long-term storage through lysosomal or endosomal pathways. By the application of precisely controlled external magnetic fields, MNP accumulation is enhanced and diffusion restricted, thereby prolonging their retention time in target tissues. These combined characteristics enable efficient targeted delivery and sustained local retention of Rosi, consequently enhancing browning effects of WAT.

Additional studies suggest that SPIONs can improve cell membrane permeability through ‘magnetic hyperthermia’ or ‘ligand-mediated endocytosis’, optimizing drug release and cellular delivery efficiency (Khaledian et al. 2020; Nieciecka et al. 2021). The former enhances membrane fluidity, promoting endocytosis for controlled drug release and reduced systemic toxicity. While ‘ligand-mediated endocytosis’ relies on surface modifications (e.g. antibodies) to enable specific binding with adipocyte surface receptors, facilitating active uptake and thereby improving targeting precision and cellular internalization efficiency. Notably, current approaches require subcutaneous magnet implantation, posing surgical risks and reducing patient acceptability. Two strategies have been proposed to overcome these limitations: development of high-penetration external magnetic fields, and engineering multifunctional MNP with intrinsic targeting capacity (Wu F et al. 2017). These integrated systems represent a new frontier in obesity research and hold promise for safer, more effective therapies.

6. Discussion

Obesity significantly elevates the risk of metabolic disorders such as diabetes, hypertension, hyperlipidemia, and cardiovascular diseases, underscoring the urgent need for more effective therapeutic strategies (Avgerinos et al. 2019; Piché et al. 2020; Artasensi et al. 2023). Browning agents that promote beige adipocyte formation and thermogenesis have garnered considerable attention as they target core pathological mechanisms of obesity (Cheng et al. 2021). However, systemic administration of such agents is often accompanied by adverse effects and limited oral bioavailability. Targeted drug delivery systems have been proposed to resolve these limitations by selectively directing browning agents to WAT. This approach offers dual benefits: minimizing off-target toxicity and enhancing local drug efficacy. Excitingly, these delivery strategies can be combined with other therapies such as PDT and PTT to achieve synergistic browning effects (Cheng et al. 2021; Ma et al. 2024). Currently, three major categories of fat-targeted delivery have emerged: (1) actively targeted nanocarriers based on ligand–receptor recognition; (2) transdermal MN systems; and (3) physical therapies such as PDT and PTT. While each method offers unique advantages, significant hurdles remain, including optimization of delivery efficiency, long-term safety validation, and scalable manufacturing. Overcoming these challenges is critical for successful clinical translation.

6.1. Challenges in targeting VAT

Human adipose tissue is broadly classified into SAT and VAT, which differ markedly in anatomical location, physiological function, and metabolic implications (Ibrahim 2010). Among them, excessive accumulation of VAT poses a particularly serious health threat due to its distinctive metabolic characteristics. VAT releases abundant free fatty acids and pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which enter into the portal circulation, promoting hepatic insulin resistance, gluconeogenesis upregulation, and subsequent development of metabolic disorders—including hypertension, NAFLD, and cardiovascular disease (Ibrahim 2010; Abraham et al. 2015; Chait and den Hartigh 2020; Nobarani et al. 2022). Clinical studies demonstrate that VAT reduction correlates with improved inflammatory markers (e.g. PAI-1) and metabolic parameters (insulin/C-peptide), suggesting its pivotal role in ameliorating obesity-related metabolic dysfunction (Castro-Barquero et al. 2023). To better quantify these risks, researchers has developed a novel metric, the Metabolic Score for Visceral Fat (METS-VF), to estimate visceral fat levels and assess cardiometabolic health. This metric demonstrates excellent performance in predicting the onset of T2DM and hypertension, with effects independent of BMI (Bello-Chavolla et al. 2020). These findings collectively underscore VAT as a high-value therapeutic target for addressing metabolic syndrome.

However, several major challenges hinder effective browning-targeted therapy in VAT. First, the inflammatory microenvironment of VAT, characterized by high levels of TNF-α and IL-6, can suppress thermogenic signaling pathways (Rajbhandari et al. 2018). A potential solution may lie in combining anti-inflammatory agents with browning inducers to enhance the browning response in VAT. Second, current fat-targeting delivery systems exhibit notable limitations, external approaches such as MN, PTT, and magnetic targeting are mostly applicable to SAT, with limited impact on VAT. Although actively targeted nanocarriers (e.g. ligand- or aptamer-modified nano-drug delivery system) can reach VAT via systemic administration, they often require intravenous or intraperitoneal injection, posing adherence challenges in clinical settings. While oral formulations have been explored, studies remain limited. Therefore, the development of a noninvasive, patient-friendly delivery system capable of efficiently targeting abdominal VAT holds significant translational potential. Additionally, obesity and its metabolic sequelae are chronic in nature. Both cold-induced and drug-induced browning of WAT are reversible processes (Roh et al. 2018). Most current studies administer treatments for only days to weeks, demonstrating short-term efficacy but leaving concerns over long-term maintenance and weight rebound unresolved. Future research should prioritize the development of post-intervention maintenance strategies to sustain therapeutic benefits and prevent relapse, ultimately enabling long-term management of metabolic diseases.

6.2. Challenges in clinical translation

The clinical translation of adipose-targeted therapies is challenged by several fundamental factors, the most critical being interspecies physiological differences (Börgeson et al. 2022). Small animals such as mice exhibit metabolic rates significantly higher than those of humans—murine hepatic blood flow can be up to ten times faster, leading to drastically different drug clearance kinetics (Kruepunga et al. 2019). Consequently, dose conversions based solely on body weight may lead to underexposure or overexposure in humans, since transitioning from small, high-metabolic-rate species to humans demands more sophisticated modeling than linear weight scaling. Beyond dose conversion, another problem is the lack of systematic preclinical validation for many advanced delivery systems (e.g. PBP-NPs, PLT3 liposomes), which have shown only proof-of-concept results in small animal models. This gap spans two key areas: (1) Immunogenicity—humans may exhibit heightened sensitivity to nanocarriers, recombinant proteins, or gene editing components than rodents (Li L et al. 2022), which potentially triggering more robust immune responses that may compromise therapeutic efficacy and elevate safety risks; (2) Targeting efficiency—anatomical distribution, adipose architecture, and metabolic regulation vary substantially between rodents and humans (Raajendiran et al. 2021). The larger body size and complex fat distribution of humans demands more robust delivery capabilities for clinical efficacy. However, most studies do not provide pharmacokinetic parameters (such as Cmax, AUC) or ‘targeting index’ (the drug concentration ratio of adipose tissue/non-target tissue), weakening the analysis of the advantages and disadvantages of the technologies. To bridge these translational gaps, several strategies are recommended: (i) Establish cross-species comparative platforms to validate pharmacodynamic and toxicological profiles in large animal models such as non-human primates; (ii) Develop predictive models using human organoids or humanized mice to assess clinical potential, and evaluate the pharmacokinetic parameters or the drug concentration ratio of adipose tissue/non-target tissue. Only through a comprehensive, multilevel translational framework can preclinical advances be effectively adapted to human therapeutic applications.

6.3. Challenges in materials optimization

Despite significant advances in adipose-targeted therapeutics—notably peptide-modified nanocarriers that induce browning in SAT and VAT, key material-related challenges persist. For instance, PLGA is a widely used biodegradable polymer in the development of nanocarriers for drug delivery due to its biocompatibility and controlled release properties. However, the degradation of PLGA into lactic and glycolic acids can lower local pH, activating the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and triggering the release of pro-inflammatory cytokines. Rapid degradation may further lead to adverse outcomes such as fibrosis or granuloma formation (Kim et al. 2021). In contrast, aptamer-modified NPs provide key advantages, including high specificity and low immunogenicity. However, several technical challenges remain. (1) Aptamer instability: Conformational changes may occur under fluctuating temperature, pH, or ionic conditions. (2) Surface chemistry heterogeneity: Uneven distribution of functional groups can reduce reproducibility. (3) High production costs: The SELEX process for aptamer selection is labor-intensive, and clinical-grade aptamer synthesis requires costly chemical modifications, purification, and quality control. These limitations hinder large-scale clinical deployment (Wu Z et al. 2011; Xiao and Farokhzad 2012). Compared to systemic delivery, localized administration offers improved bioavailability at the target site and reduced systemic exposure. MNP-mediated delivery has gained attention, yet its clinical utility is hampered by the need for surgically implanted magnets. Promisingly, physical triggers such as PDT or PTT may serve as safer alternatives to invasive procedures. Nevertheless, deep adipose tissue penetration remains a limiting factor, demanding further innovations in material design and delivery strategies to enhance transdermal efficiency.

In summary, although substantial advances have been made in fat-targeted therapy, clinical translation will require further work on optimizing carrier materials, improving delivery precision, and ensuring safety. Continued research in these areas will be crucial for moving from bench to bedside.

Funding Statement

This study was supported by research funding from Natural Science Foundation project of Sichuan Province [No. 2024NSFSC1730]; Science and Technology Strategic Cooperation Project of Luzhou Government-Southwest Medical University [2024LZXNYDJ101]. Scientific research fund of Southwest Medical University [2024ZKY026]. Chengdu Medical Research Project [2025456].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.