Fabrication and application of microneedle systems for adipose tissue reduction

Abstract

Driven by changes in modern lifestyles and growing health awareness, obesity has become a significant global public health concern. It not only impacts physical appearance and psychological well-being but also constitutes a significant risk factor for chronic diseases, including cardiovascular disorders, diabetes, and hypertension. Microneedle-based delivery of anti-obesity drugs, a novel and non-invasive technology, has attracted considerable attention in recent years. This review aims to provide a comprehensive overview of microneedle types, materials, fabrication techniques, recent advancements in their application to anti-obesity drug delivery, underlying mechanisms of action, and therapeutic outcomes. The challenges and future directions of microneedle-based weight loss strategies are also discussed. As an innovative approach to obesity management, microneedle therapy holds promising prospects for application and market potential, offering a safer, more effective, and convenient solution for individuals with obesity.

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1 Introduction

Obesity has emerged as a critical global public health concern, garnering substantial attention across multiple disciplines. According to data from the World Health Organization (WHO), in 2022, over 2.5 billion adults aged 18 years and older were classified as overweight—of whom more than 890 million were identified as obese.¹ The prevalence of obesity is also rising rapidly among children and adolescents, a trend particularly pronounced in developing countries.² Obesity is a medical condition characterized by excessive adiposity and potential adipose tissue dysfunction. Its aetiology is multifactorial and remains incompletely understood. Obesity can be broadly classified into preclinical and clinical forms (i.e., excessive fat accumulation without or with associated disease).³ Preclinical obesity denotes a condition of excessive fat accumulation wherein the functional integrity of other tissues and organs is maintained. However, the risk of progression to clinical obesity and associated comorbidities—such as type 2 diabetes, cardiovascular disease, certain cancers, and osteoarthritis—is elevated.⁴ Clinical obesity is recognized as a chronic systemic disease characterized by functional alterations in tissues, organs or systemic dysfunction caused by excessive adiposity. The revised definition of obesity no longer prioritizes body mass index (BMI) as the primary diagnostic criterion. Instead, it emphasizes overall health status, with excessive adiposity being identified through direct assessment of body fat or comprehensive clinical evaluation.⁵ Obesity and its complications diminish the quality of life and impose a substantial economic burden on global healthcare systems. It is estimated that obesity-related diseases consume hundreds of billions of dollars annually in healthcare expenditures.⁶ Furthermore, obesity negatively affects mental health, increasing the risk of psychological issues such as depression, anxiety, and low self-esteem.⁷ Therefore, the primary goals of weight loss are to improve physical appearance, enhance overall health, and elevate quality of life. Various methods are available for weight loss, including dietary control, exercise, pharmacotherapy, and surgery.^8–11 However, traditional approaches may be associated with adverse effects and complications, such as malnutrition and postoperative issues.¹² Furthermore, poor adherence, psychological burden, and unsatisfactory long-term outcomes are prevalent.^13,14 Research indicates that most individuals who lose weight tend to regain a significant portion of the lost weight within a few years.^15,16

Pharmacotherapy is currently the preferred adjunctive treatment for obesity. To date, the U.S. Food and Drug Administration (FDA) has approved six anti-obesity drugs for long-term use: orlistat,¹⁷ naltrexone/bupropion,¹⁸ phentermine/topiramate,¹⁹ liraglutide,²⁰ Ozempic²¹ and Zepbound.²² However, the effectiveness of these drugs when administered via traditional delivery methods remains limited, achieving only a 3% to 7% reduction in body weight.²³ Liraglutide and Ozempic are delivered via injection, whereas the others are administered orally.^24,25 Naltrexone/bupropion, phentermine/topiramate, liraglutide, Ozempic, and Zepbound primarily suppress appetite and enhance satiety, reducing caloric intake.²⁶ In contrast, orlistat, a lipase inhibitor, reduces caloric intake by inhibiting the absorption of dietary fat.²⁴ Despite their clinical utility, these drugs are frequently associated with side effects during clinical trials.²⁷ Recent studies have identified that β3-adrenergic receptor agonists, thyroid hormone T3, rosiglitazone (ROSI), bile acids, fucoxanthin, and curcumin^28–31 can promote thermogenesis in adipocytes and increase energy expenditure, thereby augmenting their anti-obesity effects. Numerous natural compounds, such as resveratrol and capsaicin, have also garnered significant research attention for similar properties.³² The mechanisms of action, routes of administration, and adverse effects of common anti-obesity drugs are summarized in Table 1. In recent years, emerging anti-obesity agents—including retatrutide, orforglipron, and CagriSema—have been under investigation and have demonstrated potential not only in reducing adiposity and body weight but also in improving glycemic control and blood pressure.³³ Nevertheless, obesity remains a highly complex condition that necessitates sustained, multifaceted intervention. Monotherapy often proves inadequate for achieving the goals of precision medicine, maintaining long-term efficacy, and preventing weight regain. Therefore, there is an urgent need for diversified drug delivery systems that enable the targeted administration of specific active agents, customized based on distinct etiological factors and individual patient characteristics.

Table 1 Known mechanisms, administration routes, and side effects of common anti-obesity drugs

Drug	Mechanism of action	Administration route	Side effects/limitations
Orlistat^17,18	Blocks adipose absorption	Oral	Increased gastrointestinal motility, abdominal pain, urgency of defecation
Naltrexone/bupropion^47,48	Reduces appetite, enhances satiety		Nausea, constipation, depressed mood
Phentermine/topiramate^19,49			Tachycardia, taste disturbance, paresthesia
Liraglutide^20,50		Injection	Abdominal discomfort, nausea, vomiting
Ozempic^51,52			Nausea, vomiting, and diarrhea
Zepbound^22,53			Nausea, vomiting, stomach pain and injection site reactions
β3-Adrenergic agonists^54	Promotes the browning of white adipose and increases energy expenditure	Injection, transdermal	Tachycardia
T3 (thyroid hormone)^55,56			Increased cardiovascular risk
Rosiglitazone (ROSI)^30,57		Oral, transdermal	Exacerbation of hepatic steatosis
Curcumin^31			Poor solubility
Resveratrol^58		Oral	Indigestion
Resveratrol^59			Short half-life
Capsaicin^60			Allergic reactions

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Microneedle (MN) technology has emerged as a promising transdermal drug delivery strategy, offering notable advantages such as painlessness, minimal invasiveness, and enhanced delivery efficiency.³⁴ Compared with conventional injections, MNs significantly reduce pain and improve patient compliance.^35–38 Various microneedle systems have been developed, including solid, coated, hollow, dissolvable, and hydrogel-forming types, each tailored for different delivery needs. In addition to the drug release mechanism, general characteristics of MN patches, such as mechanical strength for reliable skin penetration,³⁹ adhesion and conformability to curved skin surfaces,^40,41 drug loading capacity,⁴² and biocompatibility,⁴³ play a critical role in determining therapeutic performance. Despite continuous technological progress, several technical challenges remain, including premature patch detachment during application,⁴⁴ difficulty in penetrating thicker skin or highly keratinized skin,⁴⁵ and inconsistencies in the number of microneedles successfully inserted into the skin.⁴⁶ These features and limitations define the overall applicability of MN patches and provide the foundation for exploring their specialized use in obesity management.

In the context of obesity treatment, weight-loss microneedles represent an innovative integration of microneedle technology with anti-obesity therapeutics, offering a novel and promising strategy for effective weight management. This technology facilitates the direct delivery of fat metabolism modulators into subcutaneous adipose tissue, thereby promoting lipolysis and enhancing metabolic activity, and thus demonstrates considerable clinical potential. Moreover, microneedle-based drug delivery platforms enable precise control over dosage and release kinetics, which is critical for maximizing therapeutic efficacy while minimizing the systemic side effects commonly associated with oral or injectable formulations.⁶¹ This strategy of microneedle-mediated targeted drug delivery not only improves treatment outcomes but also mitigates the adverse effects linked to the systemic administration of anti-obesity agents. In recent years, microneedle technologies have substantially progressed across various therapeutic areas, including vaccination, diabetes management, and dermatological disorders.^62–65 These advances underscore the versatility and efficacy of microneedle-based systems in diverse medical contexts. Despite the significant burden of obesity and its associated comorbidities, the development of microneedle systems for obesity management remains in its infancy. Compared with other established indications, the field of weight-loss microneedles is characterized by limited design standardization, fragmented therapeutic strategies, and insufficient mechanistic understanding. Therefore, a systematic review is urgently needed to consolidate progress, identify critical knowledge gaps, and provide a conceptual framework for future research and clinical translation. This review provides a comprehensive overview of microneedle classifications, constituent materials, fabrication techniques, and recent advancements in the microneedle-assisted delivery of fat-reducing agents, particularly emphasizing mechanisms of action, therapeutic outcomes, and remaining challenges.

2 Microneedle systems: types, materials, and fabrication techniques

Although traditional transdermal patches have attracted considerable attention in drug delivery due to their non-invasive nature and sustained release capability, their fat reduction effectiveness is limited by these patches’ inability to penetrate the stratum corneum barrier. In contrast, microneedle patches enable efficient and controlled local drug delivery by creating uniform microchannels within the epidermis.⁶⁶ The geometry of microneedles is a critical determinant of penetration efficiency, patient comfort, and therapeutic outcome. For fat reduction applications, microneedles are typically designed with a length of 500 to 1000 μm, which allows penetration across the stratum corneum, and reach the superficial dermis while avoiding the stimulation of subcutaneous nerve endings.⁶⁷ In addition, the base diameter is generally 250–400 μm, ensuring sufficient mechanical strength, while a tip diameter of 25–35 μm provides a sharp profile that minimizes insertion force and skin trauma.^68–70 The tip spacing, usually 500–800 μm,^71,72 enables a uniform distribution of microneedles across the patch, balancing drug loading capacity with patient comfort. Previous studies have shown that shorter microneedles (<500 μm) may fail to deliver drugs effectively across the epidermis, whereas excessively long microneedles (>1000 μm) increase the risk of pain, bleeding, or nerve irritation.⁷³ Similarly, while a narrower base diameter can reduce the required penetration force, excessively slender designs compromise structural stability and may lead to needle fracture, whereas wider needles require greater force for insertion but offer improved robustness.^74,75 Furthermore, the density and array pattern of microneedles influence the balance between drug dosage, insertion success rate, and local tissue stress. In summary, these dimensional parameters collectively define the optimal design range for fat-reduction microneedles, ensuring a balance between penetration efficiency, safety, and therapeutic efficacy.

2.1 Types of MN

Microneedles used for drug delivery can be categorized based on their delivery mechanisms into solid microneedles, coated microneedles, hollow microneedles, soluble microneedles, and hydrogel microneedles. Solid microneedles are among the earliest and most extensively studied formats. They deliver drugs through a two-step process: first, the microneedle array is applied to create transient microchannels in the skin; second, a transdermal patch is applied to facilitate drug diffusion.⁷⁶ Solid microneedles offer advantages such as high mechanical strength, good biocompatibility, and low production cost, with well-established fabrication protocols.⁸⁹ However, their reliance on an additional coating or drug reservoir may restrict the types and dosages of deliverable agents.⁷⁸ Coated microneedles constitute an advanced transdermal delivery system in which therapeutic agents are applied to the microneedle surface, allowing rapid dissolution upon skin insertion and enhancing bioavailability while minimizing systemic side effects.⁹⁰ Their fabrication typically involves two steps: manufacturing the solid microneedle array, followed by drug coating using techniques such as dip coating, spray coating, drop coating, or electrodeposition.⁹¹ Hollow microneedles incorporate a central lumen extending from the tip to the base, enabling the direct delivery of liquid formulations into deeper skin layers.⁸² This design not only enhances both drug absorption and therapeutic efficacy³⁸ but also allows for the extraction of interstitial skin fluid (ISF) for diagnostic purposes.⁹² The central lumen enables precise control over drug dosage and delivery rate and is suitable for various types of drug administration. Despite these advantages, the complex and costly fabrication process and relatively low mechanical strength limit their widespread clinical use. Dissolvable microneedles, made from water-soluble or biodegradable materials, degrade or dissolve within the skin to release their payload.⁹³ The release profile is mainly dependent on the matrix composition. Their ability to eliminate biohazardous waste, with favourable biocompatibility and improved patient compliance, has made them a focal point in current research. Hydrogel microneedles consist of crosslinked polymeric networks capable of swelling upon absorbing interstitial fluid or releasing drugs via passive diffusion.⁹⁴ These systems exhibit excellent biocompatibility and offer prolonged and controlled drug release, adjustable by tuning the hydrogel's swelling behaviour.⁸⁷ However, their relatively low mechanical strength due to high water content may impair their ability to penetrate tougher skin regions. A detailed comparison of these microneedle types, including their advantages and limitations, is presented in Table 2.

Table 2 Types, advantages and disadvantages, and applications of microneedles

Types	Common materials	Methods of fabrication	Advantages	Disadvantages	Applications
Solid MNs^76–78	Metal, silicon, polymer	Laser cutting, micro-molding, electrochemical etching	High mechanical strength, resistant to breakage, capable of deep skin penetration	Requires additional coatings or auxiliary devices, making the operation complex
Coated MNs^79–81	Metal, polymer	Molding method + dip coating/spray coating/electrodeposition	Capable of rapid drug release following needle insertion, suitable for treatments requiring immediate action	Control of coating uniformity and thickness is challenging, and the drug loading capacity is limited
Hollow MNs^38,82,83	Metal, glass, polymer	Photolithography, deep reactive ion etching (DRIE)	Allows for direct injection of liquid drugs, enabling precise control of drug dosage	The preparation process is complex, costs are high, and they are prone to breakage
Soluble MNs^84,85	Water-soluble polymers (polyvinyl alcohol, hyaluronic acid, sodium alginate)	Molding method	Can completely release the drug after dissolving in the skin, eliminating the need for removal	Dissolution rate is limited by the material properties, making it unsuitable for drugs that require prolonged release
Hydrogel MNs^86–88	Hydrogel (polyvinyl alcohol, hydrogel complex)	Molding method + crosslinking curing	Highly biocompatible, suitable for prolonged drug release	Relatively low mechanical strength, prone to losing their original shape due to water absorption

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Among these microneedles, dissolvable and hydrogel microneedles are currently the most widely utilized in fat reduction applications, owing to their biocompatibility, drug-loading flexibility, and ability to provide localized and sustained release. In contrast, solid and coated microneedles exhibit more limited applicability in obesity management due to their reliance on external drug reservoirs and restricted drug-loading capacity. Nevertheless, they offer distinct advantages in terms of manufacturing simplicity, mechanical strength, and cost-effectiveness, making them attractive candidates for large-scale production. Hollow microneedles also hold promise, as they enable direct drug delivery into the dermis; however, their mechanical fragility and high cost pose significant challenges. Furthermore, future studies may explore the integration of solid microneedles with intelligent systems or auxiliary devices (e.g., ultrasound or electrical stimulation) to enhance drug diffusion and tissue permeability. Such approaches are expected to substantially broaden the application potential of solid microneedles in fat reduction therapies.

2.2 Materials of MNs

Variations in mechanical strength, biocompatibility, processability, and biodegradability among materials can significantly impact microneedle performance and safety. Therefore, careful material selection is crucial to ensure microneedle functionality and clinical safety. Based on material characteristics, microneedle materials are generally classified into four main categories: silicon,⁹⁵ ceramics,⁹⁶ metals,⁹⁷ and polymers.^79,98

In the 1990s, the first microneedles were fabricated from silicon, which provides excellent mechanical strength and manufacturing precision, making it ideal for creating precise microstructures.⁹⁵ However, silicon's relatively poor biocompatibility and non-degradability limit its suitability for long-term implantation. Consequently, silicon microneedles are primarily employed in short-term applications or high-precision scenarios.

Due to their excellent mechanical properties, high-temperature resistance, and chemical stability, ceramic materials have seen increasing use in microneedle design in recent years.⁹⁹ Common examples¹⁰⁰ include zirconia (ZrO₂), alumina (Al₂O₃), and silicon nitride (Si₃N₄), all of which exhibit good biocompatibility, thereby making them suitable for long-term applications. However, their non-degradable nature necessitates removal after use, and their brittleness may limit penetration efficiency in softer tissues.¹⁰¹ Ceramic microneedles are primarily employed in applications requiring high mechanical strength and chemical stability rather than sustained drug delivery.

Metallic materials,¹⁰² such as stainless steel and titanium alloys, provided superior mechanical strength and skin penetration capability compared with silicon and ceramics. They are resistant to corrosion and exhibit low bio-reactivity, making them effective for solid and coated microneedle applications.¹⁰³ Moreover, their non-degradable nature may trigger tissue reactions or inflammation during long-term implantation, necessitating removal after use and thus limiting their use in long-term therapeutic.

Polymeric materials are extensively utilized in microneedles, particularly in developing degradable and soluble microneedles. Commonly used polymers¹⁰⁴ include polyvinyl alcohol (PVA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), hyaluronic acid (HA), and chitosan. These materials offer a balance between sufficient mechanical strength for skin penetration, excellent biocompatibility and controlled degradability, enabling them to degrade gradually within the body and be eliminated through metabolic pathways.¹⁰⁵ Moreover, they are easy to process and fabricate, making them suitable for large-scale production. Unlike rigid inorganic microneedles, polymeric materials can be classified into two groups based on application requirements: soluble materials, such as PVA, PVP, and HA,¹⁰⁶ which dissolve after penetrating the skin to release the drug and eliminate the need for removal; and biodegradable materials, such as PLA, PLGA, and chitosan,¹⁰⁷ which gradually degrade in vivo, making them appropriate for long-term drug delivery systems. Hydrogel materials,¹⁰⁸ such as hyaluronic acid, gelatin, and sodium alginate, are also frequently employed in the design of adipose-reducing microneedles due to their high water content, soft mechanical properties, and excellent biocompatibility. Hydrogel microneedles minimize mechanical trauma to the skin and enable controlled and sustained drug release, making them particularly advantageous for gentle and prolonged drug delivery applications.

Metallic microneedles exhibit the highest mechanical strength and penetration efficiency but are limited in drug-loading capacity and long-term applications. Ceramic microneedles provide high structural precision and stability but are brittle and non-degradable. In summary, although microneedles fabricated from silicon, metals, and ceramics exhibit superior mechanical strength and precise tissue penetration, their application in adipose tissue reduction is limited by the necessity for post-application removal, poor suitability for sustained drug release, and restricted drug-loading capacity. In contrast, polymer-based microneedles, although mechanically less robust than metals or ceramics, offer sufficient penetration for adipose tissue, excellent biocompatibility, and the unique capability for controlled drug release, making them the most widely employed materials for fat-reducing applications. Such polymers enable localized fat reduction through diverse drug-loading strategies, in which active pharmaceutical agents are typically incorporated into dissolvable or hollow microneedles via techniques such as coating, mixing, or encapsulation, followed by rapid release at the target site through mechanisms including dissolution, diffusion, or microfluidic injection. Importantly, the intrinsic properties of the materials play a decisive role in determining their suitability for application in fat reduction therapies. Rigid inorganic microneedles are particularly suitable for creating skin microchannels that enhance permeability, whereas polymer-based microneedles, owing to their tunable drug-loading capacity and degradable characteristics, are more appropriate for the controlled and sustained delivery of lipolytic or browning agents.

2.3 Fabrication method of MNs

Microneedle fabrication methods are generally categorised into mould-based and direct fabrication techniques. Direct techniques primarily include laser micromachining, centrifugal lithography, 3D printing, and drawing lithography.

2.3.1 Mould method. The moulding technique involves filling a rigid microneedle mould with polydimethylsiloxane (PDMS) to produce a reusable PDMS mould. By injecting polymers, metals, or other materials into the PDMS mould and curing them, microneedles with defined shapes and sizes can be fabricated, as shown in Fig. 1. This method offers high reproducibility, making it suitable for large-scale production with good cost-effectiveness, and is compatible with various materials.^109,110 However, the fabrication of high-precision moulds, particularly at the nanoscale, poses significant technical challenges. In some cases, difficulties in demoulding may result in the breakage of needle tips. This issue can be mitigated through surface treatments or anti-adhesion coatings. The moulding method is suitable for fabricating solid microneedles, soluble microneedles, hydrogel microneedles, multilayered structures or composite microneedles. Common mould-filling techniques include centrifugal filling,¹¹¹ vacuum filling,¹¹² pressure filling, ultrasonic filling,¹¹³ permeation filling, and solvent evaporation filling.¹¹⁴

Fig. 1 (a) Schematic illustration of the microneedle fabrication process using the mold-based method (designed by the authors); (b) SEM image of microneedles fabricated via the mold-based method; this figure has been reproduced from ref. 116 with permission from Journal of Industrial and Engineering Chemistry, copyright 2024.

Among the various fabrication methods, moulding is the most widely employed technique for developing microneedle patches intended for obesity treatment, primarily due to its scalability, low cost, and compatibility with biodegradable polymers such as PVA, PVP, and HA. Nevertheless, challenges remain in achieving precise control over microneedle geometry, ensuring uniform drug distribution within the matrix, and preserving the bioactivity of embedded drugs during fabrication processes such as curing and drying. Inconsistent demoulding and variations in mould quality or filling conditions may compromise reproducibility, a critical factor in fat-reduction applications where uniform penetration depth and consistent drug release are essential for therapeutic efficacy. In addition, maintaining precise tip geometry, preventing blunting during demoulding, and achieving consistent batch to batch reproducibility remain ongoing challenges that may compromise penetration efficiency and clinical reliability.¹¹⁵ Future improvements may focus on advanced mold designs, surface modifications to facilitate stable demoulding, and integration with microfluidic-assisted filling techniques to enhance reproducibility and drug-loading accuracy. Such advancements are expected to establish the moulding method more firmly as a key technology for large-scale production of fat-reducing microneedle systems.

2.3.2 Laser micromachining. Laser micromachining is a high-precision processing technique commonly used for manufacturing microneedles, utilising the energy of a laser beam to locally melt, ablate, or vaporise materials, thereby forming fine microstructures.¹¹⁷ During processing, the laser beam, focused on a minor point, ablates the material surface, removing material layer by layer to form the microneedle structure, as shown in Fig. 2. Laser micromachining provides extremely high spatial resolution, enabling precise control over microneedle size, shape, and spacing, and thus facilitates the fabrication of complex microneedle structures.¹¹⁸ This method applies to various materials, including metals, polymers, and ceramics. However, laser processing generates localised high temperatures, which may cause thermal damage, melting, or micro-cracking at the material surface or edges, potentially compromising the mechanical properties or biocompatibility of the material.¹¹⁹ Additionally, microneedle moulds can be created by laser processing metal sheets, serving as templates for microneedle formation through casting and curing techniques. The high uniformity and repeatability of the moulds facilitate scalable production, significantly improving manufacturing efficiency and cost-effectiveness. For fat-reduction applications, laser micromachining is particularly advantageous for fabricating high-density microneedle arrays with precise geometries, ensuring predictable dermal penetration depths and thereby enhancing the reproducibility of lipolytic agent delivery. Despite these benefits, challenges remain in maintaining precise tip geometry and achieving consistent batch-to-batch reproducibility, since even minor fluctuations in laser energy, focal alignment, or scanning speed can result in variations in tip sharpness and overall microneedle dimensions.¹²⁰ These inconsistencies may compromise penetration efficiency and undermine therapeutic reliability in clinical applications.

Fig. 2 (a) Schematic diagram of the laser microfabrication setup and layer-by-layer scanning strategy (designed by the authors); (b) SEM side view and (c) top view of laser-processed conical microneedles with offset holes; this figure has been reproduced from ref. 121 with permission from Microsystems & Nanoengineering, copyright 2019; (d) and (e) SEM images of thin and thick truncated conical microneedles; this figure has been reproduced from ref. 121 with permission from Microsystems & Nanoengineering, copyright 2019.

2.3.3 Centrifugal photolithography. Centrifugal photolithography is a micro-manufacturing technique that combines centrifugal force with photolithography.¹²² This technique uniformly distributes liquid or semi-solid materials onto a substrate using centrifugal force, followed by patterning and curing using photolithography,⁸⁴ as shown in Fig. 3. Centrifugal photolithography can produce microneedles with varying geometries and sizes by adjusting the centrifugal speed and exposure time, offering advantages such as high uniformity and productivity. However, it requires precise moulds, involves significant complexity, and is limited in material selection. Yang et al.¹²³ proposed the use of the centrifugal lithography (CL) method to fabricate dissolvable microneedles (DMNs). This method involves a single centrifugation of a viscous HA solution drop to produce DMNs designed to maintain encapsulated biologics’ activity. Centrifugal lithography enables the production of uniform microneedle arrays with minimal defects, which ensures consistent insertion profiles. This reliability is especially beneficial for fat-reduction applications, where reproducible penetration depths and consistent drug distribution are critical for achieving predictable and localized therapeutic outcomes.

Fig. 3 (a) Schematic diagram of microneedle array fabrication using centrifugal lithography (designed by the authors); (b–e) SEM images of microneedles fabricated on the inner plate using CL; this figure has been reproduced from ref. 123 with permission from Advanced Healthcare Materials, copyright 2017.

2.3.4 3D printing technology. 3D printing is a rapid additive manufacturing technology broadly categorized into photopolymerization-based and extrusion-based techniques, enabling flexible customization of complex structures and personalized geometries.¹²⁴ In the 3D printing process, microneedle structures are fabricated layer by layer from a pre-designed 3D model using selected materials. Depending on the printer's resolution and material properties, the material is solidified or melted through light exposure, heat, or mechanical force, directly forming microneedles or microneedle masters. Subsequently, PDMS can be cast onto the printed microneedle masters to fabricate microneedles through a mold-based approach, as illustrated in Fig. 4. This fabrication strategy offers substantial advantages in terms of design flexibility and material versatility. Nevertheless, it remains constrained by limited printing resolution, low production efficiency, and high manufacturing costs. Various 3D printing technologies, including high-precision stereolithography (SLA), digital light processing (DLP), fused deposition modeling (FDM), and two-photon polymerization (2PP), have been employed for microneedle fabrication.^125–128 Among these, SLA achieves resolutions ranging from 10 to 150 μm,¹²⁹ whereas DLP typically attains micrometer-scale resolution depending on the material employed.¹³⁰ In contrast, FDM is less suitable for microneedle fabrication due to its limited resolution, typically between 50 and 200 μm.¹³¹ Meanwhile, 2PP can reach resolutions as low as 100 nm, demonstrating superior geometric control and making it particularly suitable for fabricating microneedles and other micro- to nanoscale precision structures.¹³²

Fig. 4 (a) Schematic diagram of the microneedle fabrication process using 3D printing (designed by the authors); (b) SEM image of a 3D-printed microneedle array; this figure has been reproduced from ref. 135 with permission from Advanced Functional Materials, copyright 2021; (c) magnified view of a 3D-printed microneedle; this figure has been reproduced from ref. 135 with permission from Advanced Functional Materials, copyright 2021.

The achievable resolution of these 3D printing methods directly influences critical microneedle features, including tip sharpness, base diameter, and overall geometry, which in turn determine penetration efficiency, insertion force, and drug delivery accuracy. For fat-reduction applications, typical microneedle dimensions (length 500–1000 μm, base diameter 250–400 μm, tip diameter 25–35 μm, and tip spacing 500–800 μm) require resolutions of at least 20–50 μm in the XY plane and 10–20 μm in the Z direction to ensure precise replication of these features. Insufficient printing resolution may produce blunt tips or irregular geometries, which may reduce skin penetration efficiency and compromise consistent drug release. SLA and 2PP can readily meet these requirements, whereas DLP may require optimization of material and exposure parameters, while FDM is generally unsuitable for fabricating microneedles with sharp tips and precise dimensions. Careful adjustment of printing parameters, including layer thickness, exposure time, and curing conditions, is therefore essential to produce microneedle masters meeting the stringent dimensional requirements for obesity treatment. For example, Fitaihi et al.¹³³ used SLA to design and optimize dissolvable PVP/PVA microneedles moulds for ocular drug delivery, systematically demonstrating how printing parameters affect structural integrity and insertion efficiency. Despite these advances, process-related challenges limit broader clinical translation. Maintaining precise tip geometry and dimensional uniformity across batches is difficult, as minor deviations in exposure dose, curing conditions, or printer calibration may lead to blunt tips or irregular geometries, reducing penetration efficiency and reproducibility.¹³⁴ Moreover, the integration of bioactive molecules is constrained by the high-energy or thermal environments inherent in many printing processes, which may compromise drug stability and uniform distribution. Addressing these limitations will require systematic optimization of printing parameters, and the development of biocompatible printable inks that preserve drug activity. Overall, 3D printing offers unmatched design flexibility and holds significant promise for patient-specific, personalized anti-obesity therapies, although current limitations in efficiency and cost hinder its widespread application.

2.3.5 Stretchable screen printing. Stretchable screen printing is a method for fabricating microneedle structures by stretching a polymer film.¹³⁶ This technique combines the deformation of elastic resetting materials with photosensitive polymer technology to create highly ordered microneedle arrays through the mechanical stretching and curing of photosensitive polymers,¹³⁷ as shown in Fig. 5. The stretchable screen printing method enables control over the length and morphology of the microneedles by adjusting the magnitude and direction of the applied forces, and the fabrication process is relatively straightforward. However, during the stretching process, temporary deformation of the materials may occur, leading to unpredictability in the final shape of the microneedles. Building upon this principle, Lee et al.¹³⁸ proposed a maskless and light-free drawing lithography technique, in which thermosetting polymers are directly stretched from a two-dimensional solid surface to fabricate ultrahigh-aspect-ratio (UHAR) microneedles with heights of up to 2 mm. This system demonstrated effective transdermal drug delivery in a diabetic rat model, with reductions in blood glucose levels confirming its hypoglycemic efficacy. Compared with other fabrication methods, this technique not only overcomes the limitation of microneedle height but also effectively addresses the challenges of penetrating the skin barrier and achieving precise intradermal drug delivery. For fat-reduction applications, the ability to fabricate tall microneedles is particularly advantageous, as it may enable deeper penetration into subcutaneous adipose tissue, thereby enhancing the localized delivery and bioavailability of anti-obesity drugs. Moreover, this technique holds significant potential for fabricating large-area, low-cost microneedle patches that can adapt to irregular body contours, thereby improving skin contact and ensuring more uniform delivery of fat-reducing drugs. Nevertheless, variability in needle morphology remains a critical challenge that needs to be addressed to ensure consistent penetration depth and drug release profiles.

Fig. 5 (a) Schematic diagram of the wire drawing lithography process (designed by the authors); (b–e) SEM images of solid microneedle arrays fabricated by the wire drawing process; this figure has been reproduced from ref. 139 with permission from Acta Biomaterialia, copyright 2018; (f–g) SEM images of biomimetic microneedles; this figure has been reproduced from ref. 139 with permission from Acta Biomaterialia, copyright 2018.

3 Applications of adipose-reduction drug delivery microneedles

With the continuous advancement of microneedle technology in transdermal drug delivery, its applications in fat reduction therapies have become increasingly versatile and promising. Microneedles, owing to their tunable dimensions, sharp geometry that facilitates painless skin penetration, and fabrication from biocompatible polymers such as HA, PVP, or PLGA, offer significant advantages compared with conventional drug administration routes. These structural and material characteristics not only determine the efficiency of skin insertion and dissolution but also facilitate the precise modulation of drug release profiles. Accordingly, microneedle-based anti-obesity systems demonstrate substantial potential in improving drug delivery efficiency, enhancing targeting precision, and enabling a broader range of therapeutic modalities. Building upon these advantages, researchers are actively exploring the integration of various fat-reducing agents, therapeutic strategies, and intelligent delivery systems with microneedle platforms to achieve safer, more effective, and patient-tailored fat-reduction interventions.

This review provides a comprehensive overview of recent advances and emerging trends in applying microneedles for anti-obesity drug delivery. The discussion centres on five key areas: (1) browning agents that induce the conversion of white to brown adipocytes, (2) regulators of lipid metabolism, (3) gene-targeted therapies, (4) multimodal synergistic treatment strategies, and (5) innovative microneedle-based carrier systems. Collectively, these innovations represent a paradigm shift toward precision transdermal therapeutics for obesity management.

3.1 Microneedle-based delivery of browning agents

White adipose tissue (WAT) and brown adipose tissue (BAT) are the two primary types of adipose tissue found in mammals. WAT primarily functions as an energy reservoir, storing excess metabolic energy in the form of triglycerides.¹⁴⁰ It is distributed in the subcutaneous layers, around visceral organs, and in regions such as the groin and mesentery.¹⁴¹ In contrast, BAT is crucial in reducing adipose accumulation by increasing energy expenditure and generating heat by activating metabolically active beige adipocytes, thereby contributing to weight loss.¹⁴² BAT is predominantly located in the neck, scapulae, and shoulders. The thermogenic response induced by BAT is mediated by the specific uncoupling protein 1 (UCP1).¹⁴³ During the tricarboxylic acid (TCA) cycle, lipid and carbohydrate catabolism generate a proton gradient across the inner mitochondrial membrane.¹⁴⁴ UCP1 disrupts ATP synthesis by uncoupling the proton gradient, thereby converting energy into heat, reducing adipose stores and enhancing energy expenditure.¹⁴⁵ However, the quantity of BAT in adult humans is limited, making it an attractive target for treating obesity and related chronic diseases.¹⁴⁶ Promoting BAT activation or inducing the browning of WAT into beige adipose tissue represents a promising therapeutic strategy for combating obesity.¹⁴⁷

Microneedles offer an exact and efficient platform for the targeted delivery of various browning agents that induce adipocyte thermogenesis and promote energy expenditure. Such agents¹⁴⁸ include β3-adrenergic receptor agonists, thyroid hormone T3, rosiglitazone (ROSI), bile acids, fucoxanthin, and curcumin. In recent years, the application of microneedle systems for delivering browning agents has significantly advanced. Zhang et al.⁶⁷ developed a nanoparticle (NP)-based methacrylated hyaluronic acid (m-HA) microneedle patch for the localized delivery of ROSI and CL 316243, resulting in substantial local fat reduction (Fig. 6a). In treated mice, body weight decreased by 15%, and epididymal white adipose tissue (EpiWAT) was reduced by 30%. Peng et al.⁶⁸ modified the backside of microneedles with black phosphorus nanosheets to enable temperature-controlled release of ROSI under near-infrared (NIR) irradiation, leading to an 83% reduction in inguinal white adipose tissue (IgWAT) and a 68% reduction in EpiWAT, demonstrating precise and effective body contouring (Fig. 6b and c). However, using NIR irradiation carries a risk of skin overheating or burns. To address this, Gao et al.¹⁴⁹ designed a biodegradable microneedle patch loaded with photothermal polydopamine nanoparticles (PDA-NPs) and the anti-obesity drug mirabegron. Upon NIR-triggered photothermal activation, the system effectively reduced subcutaneous WAT, achieving a 23% decrease in body weight, an 82% reduction in IgWAT, and a 77.6% reduction in EpiWAT (Fig. 6d–f). This technology represents a notable advancement in fat reduction strategies, achieving systemic weight loss and precise local fat targeting.

Fig. 6 Microneedle platform for the delivery of browning agents. (a) Schematic illustration of the browning reagents-loaded transcutaneous MN patch; this figure has been reproduced from ref. 67 with permission from ACS Nano, copyright 2017; (b and c) schematic illustration of the change of body shapes before and after slimming and the process of BP-Rosi-MN patch applied to the human skin; this figure has been reproduced from ref. 68 with permission from Applied Materials Today, copyright 2020; (d–f) schematic diagram of transdermal photothermal drug therapy with microneedle patches containing PDA-NPs as well as mirabegron used to inhibit adipogenesis and promote adipocyte browning; this figure has been reproduced from ref. 149 with permission from Biomaterials Science, copyright 2024; (g–i) schematic illustration of a multifunctional microneedle patch with capsaicin-loaded micelles for suppressing adipogenesis and promoting adipocyte browning; this figure has been reproduced from ref. 69 with permission from Advanced Functional Materials, copyright 2021.

Mudhol et al.¹⁵⁰ proposed a novel strategy involving a single-use transdermal patch equipped with a detachable polymeric microneedle array, designed with varying degradation profiles to enable the localized delivery of anti-obesity agents directly to subcutaneous white adipose tissue. 2,4-Dinitrophenol (DNP), a mitochondrial uncoupler, has demonstrated potent anti-obesity effects but remains limited in clinical application due to systemic toxicity. Capsaicin (Cap), a bioactive compound derived from chilli peppers, has shown promising anti-obesity potential by promoting WAT browning and inhibiting adipogenesis.¹⁵¹ However, its clinical application via oral administration is severely restricted by its high hydrophobicity, low bioavailability, and intense irritation to the oral and gastrointestinal tract.¹⁵² To address these limitations, Bao et al.⁶⁹ encapsulated Cap within α-lactalbumin (α-Lac) nano micelles (M), which were subsequently incorporated into a microneedle patch (MP) composed of HA and PVA and applied directly to adipose tissue (Fig. 6g–i). In vivo experiments in mice validated the therapeutic efficacy of this localized delivery system.

Microneedle-based delivery strategies for fat browning agents facilitate the precise targeting and controlled release of therapeutic agents within adipose tissue and significantly enhance therapeutic efficacy while minimizing systemic side effects. With ongoing advancements in materials science and manufacturing techniques, microneedle technology is expected to play an increasingly pivotal role in treating obesity. It is anticipated to enable personalized, non-invasive, and controlled interventions for fat metabolism, offering safer and more effective solutions for clinical obesity management.

3.2 Microneedle-based drug delivery for fat metabolism intervention

The delivery of small molecules or peptides to directly inhibit fat synthesis or promote fat breakdown has emerged as a promising strategy. Natural products represent a significant source of lead compounds and play a crucial role in drug discovery.¹⁵³ Various natural products, including caffeine, gelatin, hyaluronic acid, and resveratrol, have been widely applied in treating obesity. These compounds regulate obesity by stimulating lipolysis, inhibiting adipogenesis, and promoting energy expenditure. While orally administered natural products offer a safe and straightforward approach to fat reduction, their limited bioavailability constrains their effectiveness in reducing subcutaneous fat. Than et al.¹⁵⁴ studied a detachable polymeric microneedle system based on HA and PLGA, designed for the rapid delivery of CL 316243 and thyroid hormone T3 to subcutaneous WAT, enabling sustained drug release and enhanced efficacy (Fig. 7a). The results demonstrated significant reductions in body weight and local fat in mice treated with CL 316243 and thyroid hormone T3, accompanied by an improved metabolic index. The study showed that this system effectively inhibits adipogenesis, promotes lipolysis, and induces browning. Compared with intraperitoneal (IP) injections, microneedle-based transdermal delivery achieved a lower effective dose. This technology enables precise local drug delivery and offers sustained release and multiple mechanisms of action, providing an innovative, efficient, and safe solution for anti-obesity therapy. An et al.⁷⁰ explored the intradermal administration of gelatin to directly target local subcutaneous adipose tissue, inducing lipid degradation within adipocytes while inhibiting adipogenesis, thereby regulating fat metabolism and reducing fat accumulation (Fig. 7b). Both in vitro and in vivo experiments demonstrated that the gelatin microneedle system (GMNs) group exhibited a 20% reduction in subcutaneous fat weight. Local delivery of gelatin decreased lipid droplet accumulation in adipocytes, reduced the expression of pro-adipogenesis genes, and lowered local fat accumulation in vivo, thereby improving overall metabolic status. This study not only induces lipolysis but also inhibits adipogenesis, with their synergistic effects leading to more effective regulation of fat metabolism, offering a novel strategy for localized anti-obesity treatment.

Fig. 7 Microneedle platform for the delivery of fat metabolism-modulating drugs. (a) Schematic of delivery of adipose browning compounds to subcutaneous adipose tissue using a transdermal patch equipped with a dissolvable MN array; this figure has been reproduced from ref. 154 with permission from Small Methods, copyright 2017; (b) gelatin microneedles directly target the local subcutaneous adipose tissue, inducing lipid degradation within adipocytes; this figure has been reproduced from ref. 70 with permission from Acta Biomaterialia, copyright 2018; (c) soluble nanostructured lipid carrier microneedles for localized delivery of resveratrol to treat obesity; this figure has been reproduced from ref. 155 with permission from Materials Today Communications, copyright 2024; (d) illustration of dry powder microneedle-enabled transdermal anti-inflammatory therapy; this figure has been reproduced from ref. 156 with permission from Chemical Engineering Journal, copyright 2024; (e) soluble microneedle patches for localized delivery of caffeine to achieve anti-obesity effects; this figure has been reproduced from ref. 157 with permission from Journal of Controlled Release, copyright 2017.

Nayak et al.¹⁵⁵ developed a nanostructured lipid carrier (NLC) loaded with resveratrol (Res) and delivered it locally via a dissolving microneedle patch (DMP) to exert its anti-obesity effects (Fig. 7c). By formulating Res into nanoparticles and integrating them into the microneedle patch, the researchers achieved sustained release and efficient delivery, overcoming the limitations of traditional delivery methods for Res. Both in vitro and in vivo studies demonstrated that the microneedle patch significantly reduced body weight, decreased white adipose tissue, and improved metabolic parameters in high-fat diet-induced obese mice. Additionally, it notably inhibited lipid droplet accumulation in adipocytes and promoted the expression of brown adipogenesis-related genes. This microneedle system offers efficient localized drug delivery, sustained release, and multiple anti-obesity effects, providing strong technological support and a theoretical foundation for the future development of non-invasive, precise, localized anti-obesity treatments.

Zan et al.¹⁵⁶ proposed a dry powder microneedle system based on manganese dioxide nanoparticles (MnO₂) and resveratrol (Res), featuring an ultra-high loading capacity for the transdermal anti-inflammatory treatment of obesity, as illustrated in Fig. 7d. The MnO₂ nanoparticles react with hydrogen peroxide to generate oxygen, which synergizes with the natural antioxidant resveratrol to reduce oxidative stress, hypoxia, and inflammation in adipose tissue. This results in reduced white adipose tissue, improved systemic metabolism, and alleviation of conditions such as type 2 diabetes, systemic inflammation, and hyperlipidemia. The results showed that compared with the control group, the mice treated with the MnO₂-Res microneedles exhibited significantly reduced body weight and adiposity, with a 14.2% reduction in body weight, a 51.2% reduction in IgWAT, and a 36.1% reduction in EpiWAT. This dry powder microneedle system effectively reduces fat and improves other chronic conditions while possessing two orders of magnitude higher drug-loading capacity than traditional microneedles, making it suitable for long-term treatment.

Dangol et al.¹⁵⁷ loaded caffeine into a soluble microneedle patch (CMP) to achieve localized anti-obesity effects. Using microneedles to deliver caffeine to subcutaneous adipose tissue directly enhanced the local therapeutic effect and reduced systemic side effects (Fig. 7e). In biological membranes, the polymorphic transition of caffeine from an anhydrous form to a hydrated form leads to crystal growth, which limits its loading capacity. However, polymers can inhibit caffeine crystal growth, allowing for a higher caffeine loading capacity. The results showed that CMP treatment reduced the body weight of mice by approximately 13%, with no significant change in food intake. Both in vitro and in vivo experiments demonstrated that this system significantly promotes lipolysis, inhibits adipogenesis, and improves metabolic indicators such as blood glucose and blood lipid levels. The use of microneedles for localized, precise drug delivery not only enhances drug concentration at the target site but also minimizes systemic side effects.

3.3 Gene regulation and targeted therapy based on microneedles

Targeted regulation of obesity-associated genes offers a means to improve therapeutic specificity. Patients with genetic forms of obesity often exhibit limited responsiveness to conventional interventions such as dietary modification, physical exercise, or pharmacotherapy. Gene therapy, which addresses specific genetic abnormalities and enables site-specific genetic modifications, represents a promising strategy for precision-targeted treatment.¹⁵⁸ Gene therapy aims to modulate gene expression—either by upregulating or downregulating target genes—to reduce adiposity and enhance energy homeostasis. Xie et al.¹⁵⁹ developed a localized anti-obesity drug delivery platform utilizing polymer-based microneedle patches designed to deliver CL 316243 directly into subcutaneous white adipose tissue. This system employs microneedles to penetrate the skin, enabling precise delivery to the target tissue, thereby increasing local drug concentration, regulating adipocyte metabolism, and minimizing systemic side effects. Experimental results demonstrated that this platform significantly reduced body weight, with WAT mass decreased by approximately 42%, while concurrently improving metabolic parameters such as blood glucose and lipid profiles. Furthermore, it potentially induced adipose browning, thereby promoting additional energy expenditure. Notably, the dose of CL 316243 required for IP injection was nearly tenfold higher than that needed for microneedle-mediated delivery.

Liang et al.¹⁶⁰ proposed a novel anti-obesity strategy with reduced cardiotoxicity by chemically modifying the traditional mitochondrial uncoupler DNP into a more lipophilic derivative, TADNP, which self-assembles into nanomicelles. The drug was locally administered to adipose tissue via soluble microneedle patches, as illustrated in Fig. 8a–c. Mice treated with MN-TADNP exhibited an approximate 20% reduction in body weight, along with 67% and 74% reductions in EpiWAT and IgWAT mass, respectively. The study demonstrated that this delivery system significantly enhanced cellular drug uptake, induced the browning of white adipose tissue, reduced overall adiposity, and ameliorated metabolic dysfunctions while markedly minimizing systemic side effects. Integrating nanotechnology with microneedle-mediated delivery enabled precise local administration and sustained drug release, thereby improving therapeutic outcomes and reducing the toxicity typically associated with oral or injectable routes. This approach offers new avenues for the treatment of obesity and related metabolic disorders.

Fig. 8 Microneedle platform for gene-targeted therapy. (a–c) Schematic illustration of TADNP synthesis, as well as oral and microneedle-delivered TADNP nanomicelles exerting anti-obesity effects by promoting browning and inhibiting adipogenesis of white adipocytes; this figure has been reproduced from ref. 160 with permission from Small, copyright 2023; (d–g) application, mechanism of action, and fabrication method for the SA-OP (LMN) patches; this figure has been reproduced from ref. 161 with permission from Advanced Materials, copyright 2024; (h–k) a schematic illustration for the synthesis process of an MN-MP/aUCP1 patch, and the MN-MP/aUCP1 patch combined with US irradiation applied to the inguinal white adipose tissue of obese mice; this figure has been reproduced from ref. 162 with permission from Nature Communications, copyright 2025.

Choi et al.¹⁶¹ developed a soluble self-locking microneedle patch based on self-assembled oligopeptide complexes (SA-OP), designed for the delivery of short hairpin RNA (shRNA) to silence specific adipocyte genes, thereby modulating fat metabolism and exerting anti-obesity effects, as illustrated in Fig. 8d–g. The cationic oligopeptides and shRNA spontaneously form complexes via electrostatic interactions, which not only protect the shRNA from enzymatic degradation in vivo but also enhance cellular uptake in adipocytes. Experimental results demonstrated a substantial reduction in body weight (21.92%) with a notably low risk of weight regain. In addition to weight control, the treatment improved insulin sensitivity, reduced inflammation, and ameliorated hepatic steatosis. Collectively, this study achieved precise shRNA delivery and sustained gene silencing in adipose tissue, providing a novel technical platform and conceptual foundation for non-invasive, long-acting gene-targeted therapies.

Xiong et al.¹⁶² developed an intelligent microneedle-assisted CRISPR activation (CRISPRa) platform with spatiotemporal ultrasound modulation to enable obesity-targeted sonogenetic therapy by precisely regulating adipose tissue gene expression while concurrently ablating excess white adipocytes. The CRISPRa–UCP1 system was directly delivered to the target adipose regions using microneedle patches. Local ultrasound stimulation enhanced skin membrane permeability, facilitating CRISPRa vector internalization, accelerating drug release and diffusion from the microneedle matrix, and promoting gene expression activation via the CRISPRa system in target cells, as illustrated in Fig. 8h–k. Treatment with this system resulted in an 18.3% reduction in body weight, improved insulin resistance, and prevention of long-term weight regain. Furthermore, the platform demonstrated high gene activation efficiency and effectively induced the browning of white adipose tissue, thereby achieving significant weight loss and alleviating metabolic dysfunction.

3.4 Multimodal microneedle-based synergistic therapy

Integration of external physical stimuli can enhance drug penetration and therapeutic efficacy. The integration of external physical stimuli with conventional microneedle systems has garnered considerable interest, involving combinations such as microneedles with ultrasound (MN + US), electrical stimulation (MN + ES), and near-infrared (NIR) light (MN + NIR). These advanced strategies enhance drug delivery through distinct mechanisms: ultrasound increases tissue permeability, electrical stimulation enables precise control over drug release, and NIR light facilitates drug absorption via photothermal effects. Nevertheless, these techniques also pose challenges, including the need for specialized equipment, elevated operational costs, and the potential for skin irritation.

Abbasi et al.⁷² employed PLGA-based microneedles in combination with iontophoresis (INT) to deliver the anti-obesity drug metformin. This approach significantly enhanced therapeutic outcomes in obese mice by inducing the browning of subcutaneous WAT, as illustrated in Fig. 9a. Mice treated with MN + INT exhibited a 3.35-fold greater reduction in body weight, a 2.9-fold decrease in body fat percentage, and reductions in gonadal WAT (GWAT) and IgWAT mass by 2.2-fold and 1.5-fold, respectively. Moreover, the treated group demonstrated increased energy expenditure, reduced blood glucose levels, and improved glucose tolerance, collectively indicating enhanced systemic metabolic function. These findings underscore the synergistic potential of combining microneedles with iontophoresis to lower drug dosage requirements, enhance localized therapeutic efficacy, and minimize systemic side effects.

Fig. 9 Microneedle platform for multimodal synergistic therapy. (a) PLGA microneedles combined with iontophoresis (INT) enable the delivery of the anti-obesity drug metformin; this figure has been reproduced from ref. 72 with permission from Pharmaceutics, copyright 2022; (b) schematic illustration of the effervescent MN design, application, and mechanism of action; this figure has been reproduced from ref. 163 with permission from ACS nano, copyright 2025; (c) schematic illustration of the MN patch with heating and cooling treatment for local weight loss; this figure has been reproduced from ref. 164 with permission from Journal of Materials Chemistry B, copyright 2021.

Luo et al.¹⁶³ developed effervescent microneedle patches for the synergistic delivery of chitosan (COA) nanoparticles and indocyanine green (ICG), integrating both controlled drug release and localized photothermal therapy (PTT) to enhance the treatment of high-fat diet-induced obesity in mice (Fig. 9b). By leveraging COA's excellent biocompatibility and biodegradability, anti-obesity drugs were encapsulated within nanoparticles to improve stability and enable sustained release. A foaming mechanism expedited microneedle dissolution and tip separation, ensuring efficient delivery into subcutaneous adipose tissue. Concurrently, ICG-mediated photothermal effects induced the browning of white adipose tissue, thereby promoting energy expenditure. Both in vivo and in vitro results demonstrated a 37.99% reduction in body weight, a 32.38% reduction in waist circumference, diminished WAT and lipid droplet accumulation, and significant upregulation of UCP1 expression in local adipose regions. This platform successfully combined pharmacological and physical therapeutic modalities to achieve complementary and synergistic effects, effectively modulating local fat metabolism, promoting adipose tissue browning, and exhibiting excellent local safety and biocompatibility.

Peng et al.¹⁶⁴ developed a temperature-responsive dissolvable microneedle patch designed to achieve dual-mode fat reduction through local temperature modulation. This system simultaneously accelerated drug release and enhanced skin penetration while directly activating local fat metabolism and promoting the browning of white adipose tissue (Fig. 9c). Experimental results showed that treated mice exhibited approximately a 30% reduction in body weight, along with reductions of around 60% and 50% in EpiWAT and IgWAT, respectively. The temperature modulation and drug release functionalities exhibited a synergistic effect, constituting a dual-mode fat-reduction strategy that integrates chemical and physical mechanisms. This approach promoted lipolysis and induced adipose browning by altering adipocyte morphology and modulating key signalling pathways, thereby significantly enhancing therapeutic efficacy. Moreover, the system effectively reduced body weight and fat mass while improving energy metabolism and glycemic control, demonstrating high local efficacy and excellent biocompatibility.

3.5 Intelligent microneedle system based on novel carriers

Innovations in materials and structural design have significantly enhanced drug delivery efficiency. The application of multilayered and nanoparticle-integrated microneedle architectures presents numerous opportunities for effective drug targeting. Emerging delivery platforms enable precise drug quantification and controlled release, facilitating targeted deposition at specific fat depots with tunable concentrations. Moreover, these systems extend the therapeutic duration and enable responsive, intelligent release mechanisms. For example, Juhng et al.¹⁶⁵ developed a triple-layered soluble microneedle patch (TLM) based on hyaluronic acid designed for the localized delivery of liraglutide in treating obesity. The three-layered design was engineered to establish a controlled release gradient: the shield layer composed of dense HA that pierces the stratum corneum and safeguards the payload; the core layer incorporated a moderate dose of liraglutide within an HA matrix to enable sustained delivery; and the base layer, composed of HA with no drug, provided structural integrity and ensured complete penetration. Upon application, the shield dissolves first, thereby exposing the core, which then releases liraglutide into the interstitial fluid for systemic absorption. This architecture not only prevents premature drug degradation but also ensures controlled and efficient delivery, leading to significant reductions in body weight and adiposity in vivo, as illustrated in Fig. 10a. Experimental results demonstrated that mice treated with TLMs exhibited a 20% reduction in body weight and a 44% decrease in gonadal fat (GF), indicating substantial improvements in fat reduction and metabolic function. This system achieves gradient-controlled and sustained release through its multilayer architecture, directly targeting subcutaneous adipose tissue. It leverages the dual effects of liraglutide—anti-obesity action and promotion of adipose browning—to enhance energy metabolism and reduce fat accumulation. In another study, Singh et al.¹⁶⁶ reported a programmable self-boosting microneedle system (PSR-MNs) for controlled semaglutide delivery to manage obesity. MN patches were fabricated using PLGA and PVP with varying molecular weights. By selecting PLGA of specific molecular weights for each layer, the dissolution characteristics of each layer could be precisely controlled, facilitating sequential semaglutide release at seven-day intervals following a single administration. The PSR-MN platform integrates an initial burst-release microneedle patch (IBR-MN) and three programmed delayed-release patches (PDR-MNs), with each layer engineered to dissolve at a predetermined time to achieve controlled, staged drug delivery (Fig. 10b–d). Experimental results indicated that the PSR-MN system effectively suppressed appetite, increased satiety, and promoted significant weight loss. Based on soluble microneedle technology, this layered-release strategy modulates the dissolution rates of individual layers, achieving time-controlled, staged drug delivery from a single administration. This approach enhances patient compliance and demonstrates superior therapeutic efficacy in obesity management.

Fig. 10 Intelligent microneedle platform with novel carriers. (a) Schematic illustration of the fabrication and administration of the triple layer microneedle (TLM); this figure has been reproduced from ref. 165 with permission from Lab on a Chip, copyright 2023; (b–d) semaglutide programmed scheduled release microneedles (PSR-MNs) to treat type 2 diabetic and obesity patients for a month via a single-administration; this figure has been reproduced from ref. 166 with permission from Advanced Therapeutics, copyright 2024; (e) engineering of the soluble rosiglitazone nanoparticle microneedle patch and (f) mechanism illustration for the treatment of obesity; this figure has been reproduced from ref. 167 with permission from Biomaterials, copyright 2024.

Chen et al.¹⁶⁷ developed a rapidly adhesive, soluble microneedle patch–referred to as HORN-MN—composed of hyaluronic acid (HA) and oleanolic acid (OA)—designed to improve the inflammatory microenvironment of subcutaneous adipose tissue and induce adipocyte browning. This system utilizes acid-degradable rosiglitazone nanoparticles as a delivery platform to enhance drug stability and regulate release kinetics (Fig. 10e). Upon microneedle dissolution, the nanoparticles were internalized by local macrophages and white adipocytes, where they underwent lysosomal degradation, leading to the gradual release of rosiglitazone. This mechanism facilitated the transdifferentiation of white adipose tissue into brown or beige adipocytes, enhancing energy expenditure and promoting lipid metabolism (Fig. 10f). In vivo studies demonstrated that treatment with HORN-MNs resulted in approximately a 17% reduction in body weight and a 48% decrease in total fat mass. Furthermore, the expression of UCP1 in white adipose tissue was significantly upregulated, indicating activation of thermogenic pathways. Overall, the system effectively reduced body weight and adiposity, ameliorated inflammation and metabolic dysfunction, and exhibited favourable local biocompatibility, which underscores the advantages of integrating nanoparticle carriers with microneedle matrices to achieve site-specific, stimuli-responsive drug release.

Despite these promising outcomes, several key challenges remain. First, nanoparticle-based carriers may elicit immunogenic responses or local inflammation upon repeated administration, potentially compromising tissue compatibility and long-term safety. Second, the large-scale fabrication of multilayered or nanoparticle-integrated microneedles remains challenging due to the requirements for precise layer alignment, reproducibility, and controlled drug loading. Addressing these challenges is essential for the clinical translation of advanced microneedle systems. Future studies should focus on optimizing carrier composition, minimizing immunogenicity, and developing scalable manufacturing techniques to ensure both safety and clinical viability.

4 Challenges and perspectives of adipose loss MNs

Although previous reviews have discussed the challenges associated with microneedle applications—such as biosensing, vaccine delivery, and general drug delivery—particularly regarding drug uniformity, process stability, and storage conditions, the present review focuses on anti-obesity applications. It highlights key challenges related to the loading efficiency and storage stability of macromolecules and complex biologics, the achievement of sustained release kinetics, the precision of targeted delivery to subcutaneous adipose tissue, and the clinical and economic feasibility of these interventions.

4.1 Challenges in the preparation and storage of adipose loss MNs

A key challenge in the fabrication of fat-reducing microneedles is achieving uniform and efficient drug loading.¹⁶⁸ Inaccurate dosing resulting from uneven drug distribution can significantly compromise therapeutic efficacy. Common loading techniques include solvent casting,¹⁶⁹ spray drying,¹⁷⁰ and mold casting.¹⁷¹ However, solvent casting may lead to non-uniform drug distribution due to variations in drug solubility and chemical stability. Precise control over the mould structure and dimensions is essential in mould casting to ensure consistent drug content. Furthermore, drug degradation may occur upon exposure to high temperatures, organic solvents, or light,¹⁷² particularly for thermosensitive and labile biomolecules such as proteins¹⁷³ and nucleic acids,¹⁷⁴ highlighting the importance of tight control over environmental conditions during fabrication.

During storage, fat-reducing microneedles must maintain drug stability and bioactivity.¹⁷⁵ Environmental factors such as humidity, temperature, and light can accelerate drug degradation.¹⁷⁶ For example, some drugs may undergo hydrolysis under high humidity, leading to reduced therapeutic efficacy.¹⁷⁷ Prolonged storage can also alter the physical properties of microneedle materials, resulting in increased brittleness or mechanical failure, which compromises skin penetration capability.^178–180 External mechanical stresses during storage or transportation, such as compression or vibration, may also cause structural damage or deformation.¹⁸¹ Therefore, protective strategies—such as moisture-resistant packaging, vacuum sealing, and shock-resistant storage—are essential to preserve microneedle integrity.^182,183 Although low-temperature storage can enhance the stability of certain thermosensitive drugs, it also presents logistical challenges and increases both storage and transportation costs.¹⁸⁴

4.2 Challenges of adipose loss MNs in obesity treatment

4.2.1 Drug delivery efficiency. Microneedles must penetrate the stratum corneum efficiently to deliver therapeutic agents to target tissues.¹⁸⁵ However, interindividual skin thickness and density variations can lead to inconsistent drug deposition and reduced delivery efficiency.¹⁸⁶ Typically, skin thickness in non-obese individuals ranges from 0.8 to 1.2 mm, whereas in obese individuals, it increases to approximately 1.5–2.3 mm.¹⁸⁷ The thicker and less uniform skin structure in obese patients poses additional challenges for microneedle insertion and uniform drug delivery. Moreover, anti-obesity treatments often rely on macromolecular or biological agents,¹⁸⁸ such as peptides and proteins, which generally exhibit limited encapsulation and release efficiencies in microneedle systems. Additionally, the diffusion and stability of these drugs within the skin may be influenced by the cutaneous microenvironment, ultimately impacting therapeutic outcomes.¹⁸⁹

Adjustable-length microneedles represent a promising strategy, enabling clinicians to tailor penetration depth according to individual skin thickness and thereby improving drug delivery precision across diverse patient populations. Moreover, the integration of microneedles with permeation-enhancing strategies—such as surfactants, fatty acids, ultrasound, or radiofrequency—can reduce insertion resistance and enhance the intradermal diffusion of macromolecular therapeutics. In addition, incorporating feedback-responsive systems into adaptive microneedle patches allows dynamic regulation of insertion depth and release kinetics in response to local tissue conditions. Collectively, these approaches may improve dosing consistency and expand the clinical applicability of microneedle-based therapies for obesity management.

4.2.2 Selection of MN materials and biocompatibility. In the treatment of obesity, the selection of microneedle materials must balance mechanical robustness, drug-loading efficiency, and biocompatibility. Because obese patients typically present with a thicker stratum corneum and dermis, microneedles must possess sufficient mechanical strength to penetrate the skin reliably and ensure consistent drug delivery. Polymers and composite materials are currently the most widely employed matrices, as their physicochemical properties critically influence drug encapsulation capacity, release profiles, and therapeutic efficacy.⁷⁹ Among these, HA, PVA, and PVP are the most commonly used water-soluble polymers, which enable rapid and minimally invasive skin insertion while allowing dissolution-mediated drug release. In contrast, biodegradable polyesters such as PLA and PLGA degrade more slowly, making them particularly suitable for sustained or staged release applications.¹⁹⁰ Notably, variations in polymer composition and concentration can markedly alter dissolution times, release kinetics, and drug stability, thereby directly influencing fat-reduction efficacy.¹⁹¹ Although polymer microneedles generally exhibit favorable biocompatibility, long-term or repeated application may still elicit immune responses or cause local inflammation.¹⁹² Therefore, during the design and clinical development phases, comprehensive long-term safety evaluations is essential. To facilitate comparison, Table 3 summarizes the most commonly employed materials for microneedle fabrication in adipose tissue reduction, highlighting representative combinations, concentrations, mechanical strength, and key features for anti-obesity application. Overall, rational material selection and optimization remain essential for advancing microneedle-based obesity therapies toward clinical translation and facilitating sustained patient adherence.

Table 3 Summary of microneedle materials, formulations, mechanical strength, and anti-obesity applications

Material	Concentration/formulation (% w/v)	Mechanical strength (N/needle)	Key features for anti-obesity application	Ref.
HA	2% HA (200–400 kDa)	∼0.18 (fracture)	Good mechanical properties, excellent biocompatibility, supports photothermal fat browning	Z. Gao et al.^149
	20% oligo-HA (10 kDa)
	3 : 7 w/w
PVA	15 wt%	∼2 N (insertion)	Excellent biocompatibility, fast-dissolving, temperature-sensitive release, supports dual-effect fat reduction	H. Peng et al.^164
Hyaluronic acid methacrylate (m-HA)	4% m-HA	∼3.5 N (loading)	Excellent biocompatibility, controlled photothermal response, supports localized fat metabolism	Y. Zhang et al.^67
	0.5% photoinitiator
	2% N′-methylene bis (acrylamide)
PLGA + HA	50% HA (10 kDa)	∼0.05 (axial)	High drug-loading capacity, tunable dissolution rate, enables sustained subcutaneous drug delivery	A. Than et al.^154
	20% PLGA (LA : GA = 50 : 50)
PLGA + PLA	2.5% PLA	∼0.3 (axial)	Slower degradation, suitable for staged or long-acting release systems, enhances fat-reduction efficiency	Y. Xie et al.^159
	22.5% PLGA (LA : GA = 50 : 50)
PLGA + PVP	10% PVP	∼0.22 (fracture)	Single-administration self-enhancing release, supports adipocyte browning and prolonged therapeutic effect	P. Singh et al.^166
	PLGA 1 (LA : GA = 50 : 50, 15 and 30 kDa)	∼0.058 (axial)
	PLGA 2 (50 : 50, 45 kDa)
	PLGA 3 (50 : 50, 60 kDa)
HA + PVA	HA : PVA = 2 : 17 (w/w)	∼0.4 (fracture)	High drug-loading, regulates adipocyte browning and lipogenesis, improves local drug concentration in adipose tissue	S. Liang et al.^160
HA + nanoparticles	5% HA	∼0.22 (fracture)	Photothermal-responsive, controlled dissolution, promotes localized WAT browning	L. Li et al.^71
	50% Fe3O4 NPs

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4.2.3 Clinical applications and economic viability. Obesity is a chronic disease that typically requires long-term treatment. Soluble microneedles are composed of water-soluble or biodegradable polymers, and function based on the principle of “single-dose delivery and needle body dissolution”.¹⁹³ The advantages of this approach include eliminating cross-contamination risks associated with secondary sterilization and repeated use,¹⁹⁴ as well as a relatively straightforward manufacturing process that facilitates uniform drug loading. However, the necessity for replacement after each treatment leads to increased material consumption, resulting in higher unit costs over the course of long-term therapy. In contrast, metal or ceramic microneedles offer greater mechanical strength and stability, theoretically permitting reuse following high-temperature sterilization.¹⁹⁵ Nevertheless, repeated use may cause needle tips to lose their original piercing performance due to fatigue or edge wear, potentially resulting in local irritation or tissue damage. Additionally, stringent cleaning, recycling, and sterilization requirements can elevate operational and management costs.

From a comprehensive perspective, for obesity treatments that require continuous and long-term drug administration, soluble microneedles—designed for single-dose applications—offer advantages in terms of biocompatibility and ease of use. However, the long-term accumulation of material costs must be carefully considered. In contrast, metal or ceramic microneedles, while potentially offering economic benefits through reusability, require consistent mechanical performance and effective sterilization after each use to prevent secondary harm. According to market research reports, the global microneedle drug delivery system market is expected to reach approximately $3.2 billion by 2025. For laboratory-scale production of soluble microneedle patches, the estimated per-piece production cost is of the order of ten dollars, while the final retail price is likely to range from $20 to $50 per patch, factoring in costs associated with packaging, quality control, regulatory approvals, and market promotion.^196,197

In comparison, although metal or ceramic microneedles have higher material costs per unit, the cost per treatment after repeated use may be lower than that of disposable polymer microneedles, provided that sterilization procedures and equipment durability are strictly maintained. Overall, with the continuous optimization of manufacturing processes and the realization of large-scale production, both types of microneedle device could achieve cost advantages. However, different materials’ cost structure, clinical applicability, and dosing frequency determine their respective market positioning and economic models. Future clinical studies and health economics evaluations should further elucidate their economic benefits and market acceptance.

5 Conclusion and outlook

Obesity has emerged as a global public health issue affecting individuals across all age groups, including the elderly, adults, pregnant women, and adolescent males. It is associated with a spectrum of pathophysiological complications, such as chronic low-grade inflammation, vascular dysfunction, thrombosis, and progressive organ damage, which can ultimately lead to a variety of comorbidities and life-threatening conditions. Despite significant advances in clinical management, the effective treatment of obesity remains a major challenge. Conventional therapeutic approaches, including oral and subcutaneous drug administration, are often constrained by poor bioavailability, nonspecific targeting, and adverse side effects, all of which contribute to suboptimal efficacy and reduced patient compliance. As an emerging drug delivery strategy, microneedle technology offers promising solutions for the local administration of anti-obesity agents. Its advantages include painlessness, minimal invasiveness, sustained release, and enhanced local drug concentration. This review provides a comprehensive overview of microneedles’ types, materials, and fabrication methods, with a particular focus on their applications in delivering anti-obesity drugs. Key formulation parameters are also discussed, including drug loading, distribution uniformity, environmental responsiveness, and long-term stability. Preclinical studies have demonstrated that microneedle systems enable efficient, low-dose drug delivery while mitigating systemic side effects, offering a promising platform for enhancing anti-obesity therapy. Furthermore, packaging strategies such as moisture-proofing, vacuum sealing, and low-temperature storage play an essential role in preserving drug bioactivity and ensuring treatment consistency over extended periods. Nevertheless, the clinical translation of microneedle-based anti-obesity therapies is still nascent, primarily limited to laboratory research and early-phase clinical trials. Comprehensive evaluations of long-term safety, therapeutic efficacy, and industrial-scale manufacturing are crucial to enabling broader clinical adoption.

Although most current pharmacological agents targeting adipose tissue remain at the experimental stage, microneedle technology has demonstrated significant advantages in enabling low-dose, site-specific drug delivery. Future research should not only identify and evaluate new anti-obesity candidate drugs but also explore combination therapies to fully leverage the localized and efficient delivery capabilities of microneedles. For instance, microneedles could be combined with localized cryolipolysis, radiofrequency, or ultrasound therapies, which mechanically or thermally disrupt adipocytes and thereby enhance the penetration, distribution, and efficacy of encapsulated agents. Such hybrid strategies may achieve synergistic fat reduction by coupling drug-mediated modulation of lipid metabolism with physical adipocyte disruption, ultimately providing superior therapeutic outcomes compared with either modality alone. Meanwhile, other non-invasive delivery platforms, such as needle-free high-pressure jet injectors, have exhibited advantages in device maturity, low-dose delivery, and cost-effectiveness. Microneedles offer superior spatial precision and drug distribution uniformity compared with these systems. However, challenges such as single-use limitations and relatively high manufacturing costs persist. Therefore, systematic comparative studies are needed to assess different technologies’ delivery efficiency, patient compliance, cost-effectiveness, and safety. Such analyses are essential for clarifying clinical indications and limitations, providing a robust scientific basis for clinical decision-making. With the integration of sensor technology and wearable electronics, innovative fat-reduction microneedle systems with real-time monitoring functionalities are anticipated. These systems may enable precise spatiotemporal control of drug release by continuously monitoring local drug concentrations, temperature, and tissue responses. Furthermore, microneedle geometry and dimensions could be personalized based on individual skin properties and subcutaneous fat distribution, facilitating precision therapy. From a translational perspective, the commercial adoption of microneedle technology remains constrained by production cost and scalability challenges. Future efforts should prioritize the development of novel biomaterials and advanced fabrication techniques, alongside comprehensive health economic evaluations to assess the cost–benefit ratio and market potential of microneedles in long-term obesity management.

In conclusion, although microneedle technology for anti-obesity drug delivery is still in its infancy, it offers distinct advantages over conventional and needle-free delivery methods, particularly regarding targeted drug localization, reduced systemic side effects, and improved patient adherence. With ongoing advances in drug optimization, refinement of delivery strategies, and integration with physical fat-reduction technologies, microneedles are anticipated to advance into a safer, more convenient, and cost-effective therapeutic modality for obesity. This advancement, in turn, may accelerate the clinical translation of experimental therapies and achieve the goal of precise, localized adipose tissue reduction.

Author contributions

Tuling Cai: preparation of the published work, specifically writing the original draft, including substantive translation. Minghao Guo: presentation of the published work, specifically visualization of figures. Si Qin, Dawei Sun, Xiao Yu and Chengyong Wang: participation in the discussion of the original draft preparation and provision of revision suggestions. Zhishan Yuan: conceptualization, supervision, funding acquisition and preparation of the draft.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research data, software or code are included in this review, and no new data were generated or analysed as part of this study. All information is derived from previously published literature.

Acknowledgements

This research was supported by Specific Discipline Construction Project of Guangdong Provincial Department of Science and Technology for Higher Education Institutions (26331100401), National Natural Science Foundation of China General Program (51975133).

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