Traditional Chinese medicine ingredients integrated microneedles: A promising strategy for transdermal treatment

Abstract

Traditional Chinese medicine (TCM) has abundant medicinal resources and distinctive pharmacological properties. So, TCM presents considerable promise in clinical treatments. However, challenges such as poor bioavailability hinder broader clinical adoption of TCM. Microneedles (MNs), an innovative and minimally invasive transdermal platform, have emerged to enhance the therapeutic performance of TCM. The integration of MNs with TCM (TCM-MNs) overcomes key limitations of conventional administration routes to reach more targeted and efficient delivery. The structural and compositional diversity of TCM ingredients necessitates diverse TCM-MNs designs, especially “unification of medicines and excipients”. Moreover, TCM-MNs can achieve synergistic benefits when combined with modality-specific interventions, like acupuncture. This review outlines advantages and types of TCM-MNs, according to the special structure and function of TCM components. Current applications of TCM-MNs in different diseases are also discussed. The review offers a promising foundation for the advancement and clinical translation of TCM-MNs in transdermal therapy.

Graphical abstract

TCM-MNs offers a means to TCM with enabling more precise and effective drug delivery. The structural and compositional diversity of active TCM constituents made diverse TCM-MN designs, particularly in terms of unification of medicines and excipients. TCM-MNs can also be combined with modality-specific therapies, including acupuncture, to achieve synergistic therapeutic outcomes, to apply in both dermatological and systemic disorders. These developments offer a promising foundation for the continued advancement and clinical translation of TCM-MNs in transdermal therapeutic interventions.

1. Introduction

Traditional Chinese medicine (TCM) is a foundational element of ancient Chinese science and culture. Guided by the principles of syndrome differentiation, TCM plays a pivotal role in disease prevention and treatment for millennia [1,2]. Within TCM, Chinese herbal medicine (collectively referred to as TCM here) comprises a wide array of active ingredients to exert therapeutic effects. The features have helped TCM to contribute to the management of various pathological conditions, including cancer [3], autoimmune disorders [4], metabolic and allergic diseases [5], and wound healing [6].

Modern applications of TCM typically involve some primary forms, mainly including single active ingredient, plant-derived extracts and classical TCM prescriptions [7,8]. TCM constitutes a valuable reservoir for novel drug discovery. Advances in TCM analysis and pharmacology have facilitated the identification of numerous active constituents, such as alkaloids, flavonoids, saponins, polysaccharides and so on. TCM is characterized by diverse bioactivities, unique structures and better safety [9]. It is well known that ginsenosides with immunomodulatory effects [10], curcumin with anti-inflammatory properties [11], and artemisinin as a potent antimalarial agent [12].

TCM offers therapeutic benefits across a wide spectrum of diseases. Nevertheless, the clinical translation and new drug development of many active ingredients are hampered by poor solubility, limited permeability and low chemical stability [13,14]. Oral administration is the predominant route of TCM in clinical. However, oral often suffers from first-pass hepatic metabolism, gastrointestinal degradation and other drawbacks. Intravenous injection can bypass above issues, but lead to nonspecific distribution and systemic toxicity [15,16]. Accordingly, skin draw attention as a promising delivery route. As the largest organ, skin provides both localized and systemic access to circulation, and become a good way to circumvent hepatic metabolism and gastrointestinal degradation [17,18]. Nevertheless, effective transdermal delivery of TCM is constrained by skin barrier. Stratum corneum limits the permeation of conventional formulations like creams, powders and hydrogels, even with the help of chemical enhancers [19].

Microneedles (MNs) as a innovate transdermal drug delivery systems (TDDS) overcomes limitations by controlling TCM delivery [20,21]. MNs are minimally invasive arrays with 25–2000 µm length needles, which are able to penetrate stratum corneum and create transient microchannels to deliver agents into targeted tissue layers [22,23]. MNs promote the administration of small molecules, macromolecules [24,25], nanoparticles [26], and complex TCM constituents. Meanwhile, it can preserve physicochemical properties and pharmacological activities of loaded drugs [27,28]. MNs have been proved clinical success in the administration of chemical drugs, antibodies, and nanovaccines [29], offering a potential platform for TCM application. The combination of MNs with TCM (TCM-MNs) retains the inherent benefits of TCM to exert multi-functionality and reduced toxicity by improving delivery precision [30]. Moreover, the variability of MNs design can accept the “unification of medicines and excipients” of TCM and accommodate the structural complexity of TCM [31,32].

Consequently, this review first outlines the fundamental advantages and major types of MNs in TCM delivery. Then different integration strategies of TCM-MNs are discussed, which include formulation challenges due to distinct physicochemical characteristics of TCM. The current and emerging applications of TCM-MNs in treating both cutaneous and systemic diseases are also examined. Finally, existing challenges and future directions for clinical translation of TCM-MNs deserve attention and recognition (Scheme 1).

Scheme 1.

Illustration to the combined forms of TCM-MNs and their application in various diseases.

2. Advantages of MNs in TCM transdermal administration

TDDS have gained popularity due to high patient compliance. Creams, hydrogels, patches and other traditional TDDS are all continually optimized. Modern technologies are developed to apply electroporation, iontophoresis, laser ablation and ultrasound in transdermal administration [[33], [34], [35]]. Each TDDS has own properties and features (Table 1), and the ultimate goal is to select an appropriate method to maximize TCM benefits.

Table 1.

The advantages and disadvantages of different transdermal delivery methods.

Category	System	Advantages	Disadvantages
Traditional method	Ointments	High drug loading capacity; moisturizing; good oxygen permeability	Unsuitability for large doses to irritate the skin; lack of surface evaporation; greasy and difficult to remove; unable to effectively deliver natural products with high molecular weight to the deeper skin
	Microemulsion/nanoemulsion	Larger specific surface area for improved absorption and optical transparency; easy to prepare, low cost; reduce drug irritation and side effects	Thermodynamically unstable prone to disintegrate due to various chemical or physical process
Advancement method	hydrogel	Three-dimensional structures composed of hydrophilic polymers linked through physical or chemical cross-linking bonds; easy to spread, comfortable, non-greasy, easy to wash and moisturizing	Suitable for loading compound with molecular weight of <500 daltons and water-soluble compounds; weak tensile strength leading to early drug release
	Microneedle	Enhance delivery by creating microchannels to bypass the skin’s natural barriers; enable good absorption of drugs; painless or minimally painful; safe and easy to operate; diverse types, various materials to match different drugs	Low drug loading capacity
	Electroporation	Form temporary hydrophilic channel on the skin surfaces, by applying the instantaneous high-voltage electric pulse field; good safety and strong immune response	Expensive equipment is required; inconvenient for patients to operate by themselves
	Iontophoresis	Non-invasive, high success rate, simplicity, and good security; can combine with acupuncture to further improve the absorption, improve the therapeutic effect
	Ultrasound facilitation	Induces skin cavitation by ultrasound, briefly damage the skin and promoting drug penetration; can adjust the frequency, intensity, and duration of ultrasonic waves according to demand

MNs consistently provide superior permeation rates and efficacy, while conventional TDDS with additional enhancers are still difficult to achieve comparable results. α-arbutin is a skin-lightening agent with limited dermal penetration. Aung et al. loaded α-arbutin in dissolvable MNs. The α-arbutin MNs exhibited a 2.8-fold increase in skin permeation compared to commercial topical creams [36]. Regarding bioactive compounds with a narrow therapeutic index, it showed that MNs have better pharmacokinetic profiles compared with microemulsions or lipid carriers to ensure safety. For aconitine, MNs helped to minimize plasma concentration fluctuations and enhanced drug stability, which mitigated toxicity risks and broadened the clinical application [37,38].

Several physical techniques can temporarily disrupt the skin barrier to enhance transdermal penetration by iontophoresis, ultrasound, electrical stimulation or laser ablation [39]. Electroporation-assisted injection of sinomenine rapidly alleviated joint pain and stiffness in elderly patients. And iontophoresis combined with acupuncture to increase drug absorption and therapeutic efficacy. However, physical techniques require specialized and costly equipment and are not easily self-administered. In other words, MNs is a more practical option for TCM applications owing to the simplicity.

Moreover, skin as an immune organ, contains a dense network of immune cells and lymphatic vessels [[40], [41], [42]]. MNs deliver therapeutic agents to dermal immune cells and adjacent lymphatic and vascular structures, after bypassing stratum corneum [43,44]. Clinical studies further demonstrate that MNs are able to transport immunotherapeutic agents into lymph nodes via lymphatic vasculature, finally to amplify localized immune responses [45]. It highlights the potential of MNs to deliver immune adjuvants and vaccines [46]. Some polysaccharides, flavonoids and saponins can act on immune cells and cytokine networks to activate immune responses [47,48]. Triptolide (TP) is valued for potent anti-inflammatory and immunosuppressive activities [49]. When delivered via MNs, TP exhibited superior penetration and distribution in inflamed joints, where immune cells were filled. MNs reached better antiinflammation and reduced systemic toxicity compared with intra-articular injection [50,51]. Overall, TCM-MNs ensure efficacy and safety simultaneously. And TCM-MNs can be self-administered without specialized equipment or complex procedures. It represents that TCM-MNs promote the clinical translation of TCM across diverse disease settings [[52], [53], [54]].

3. MNs types used for TCM-MNs

3.1. Appropriate MNs type for TCM-MNs

Based on drug delivery mechanisms, MNs can be broadly classified into five categories: solid, coated, dissolvable, hollow and hydrogel MNs [55,56]. It is critical to select appropriate MNs type for successful formulation and delivery of TCM.

Solid MNs are commonly fabricated by silicon or metal with low biocompatibility. The “Poke and Patch” approach of solid MNs pretreat skin with microchannels for subsequent drug permeability [57]. Coated MNs operate through “Coat and Poke” strategy. Drugs are sprayed or layered onto the needle surface [58]. However, the low encapsulation efficiency is unsuitable for complex TCM compounds. Thus, neither solid nor coated MNs are optimal for TCM-MNs preparation. Hollow MNs follow the principle of “Poke and Flow”. Hollow MNs deliver drugs under extra pressure and can achieve rapid and large-scale administration, which is suitable for TCM delivery [59]. Nonetheless, complicated fabrication, high costs, needle blockage and leakage limit the application of hollow MNs. Hydrogel MNs represent another option and are fabricated with swelling polymers. The drugs are embedded at needle tips, which swell upon after insertion to create channels and allow sustained release [60]. But application of hydrogel MNs is limited by the complexity of both preparation processes and chemical properties of TCM ingredients (Table 2).

Table 2.

Common types of MNs for TCM transdermal delivery.

Type	MNs	Material	TCM ingredients	Properties	Function	Ref
Dissolvable MNs	BR-CS MNAs	Chitosan	Berberine (BBR)	Needles length 800 µm; more effectively permeated to epidermis and dermis regions than gel and BR-HA MNAs	Antimicrobial activity	[73]
	ICG-ELE-MN	PDMS	Elemene (ELE)	Two-layer MNs; the gas permeable to promote the transdermal release; needles length 1000 nm; detected minimal quantity of the drug at 2 h, drug release gradually leveled off after 16 h and decreased at 22 h; the drug amount released was 49.01 µg	Combined chemotherapy and TCM; inhibited melanoma tumor growth	[74]
	Shikonin HA MN	HA	Shikonin	Drug loading 30.76 ± 0.98 µg shikonin per patch; needles length 1000 µm; a force >0.7 N/needle; improved biocompatibility	Reduced the viability and proliferation of fibroblasts and downregulated the fibrotic-related genes in hypertrophic scars	[75]
	TA and LIC DMNs	PVA, PVP	Tranexamic acid (TA) and licorice extract (LIC)	Needles length 500 µm; active ingredients directly act on melasma sites to increase the local drug concentration with a cumulative quantity of 977.46 µg TA; good pharmaceutical stability; increased bioavailability >1.3 times compared with oral	Induced melanin deposition; synergistic therapy in melasma	[76]
	EGCG/AA-loaded MNs	Poly-γ-glutamate	Epigallocatechin gallate/L-ascorbic acid	Needles length 600 µm; sustained release for 6 d; penetrate through the stratum corneum and directly deliver drugs into the upper dermal layer	Exerted antioxidant, anti-inflammatory and immunomodulatory; alleviated Th2-polarized allergic responses in AD	[77]
	GA + QAGN-loaded MN	Gel	Gallic acid (GA) and quercetin	Needles length 600 µm; inserted to a depth of 500 µm in skin; mechanical strength >2 N; dual-drug release at different periods	Erase the generation of ROS; downregulated gene expression of fibroblasts; prevented keloid scar formation	[78]
	B/S-TM@MN	Carboxymethyl cellulose	BBR and sinomenine	Needles length is 600 µm; the average fracture force of 0.19 N per needle; rapid dissolvable capacity	Alleviated inflammation and inhibited angiogenesis in RA	[79]
	BMNs	BSP	BSP	Needles length 781.9 ± 13.1 µm; bending force 25.44 ± 2.78 N; excellent moldability; insertion depth (170–215 µm) and gradually dissolve in vivo	/	[80]
Hydrogel MNs	BBRMN	Natural aloe polysaccharide and water chestnut starch	BBR and aloe polysaccharide	Needles length 700 µm; bearing capacity was 1.0 N; maximum swelling time 180 min; swelling rate 240%; stably released within 24 h	Non-antibiotic approach; prevented bacterial infection; promoting healing function in wound	[60]
	EGCG-HP MN	EGCG-phenylboronic acid modified HA-gel	MTX and EGCG	Needles length 650 µm; a force of 0.4 N/needle; minimally invasive; EGCG as high as 33.3 wt%; high sensitivity to H2O2	Antiproliferative and anti-inflammatory to improve treatment in psoriasis	[67]
Hollow MNs	HYP-NLCs in hollow MNs	AdminPen™ metallic hollow MNs	Hypericin	Efficiency entrapment was about 98.24% ± 0.06%; a dermal penetration percentage of 100%; effective hypericin delivery to the affected psoriatic area; lower total treatment costs	Decreased the levels of NF-κB, IL 6, MMP1, GSH, and catalase in psoriasis	[59]
Responsive MNs	P-M@TP	PVA, polydopamine-MXene	Triptolide and paeoniflorin	Needles length 1000 µm; endure forces exceeding 0.9 N; a light-pH dual-responsive system	Reduced collagen deposition and epidermal thickness, ameliorated skin fibrosis and capillary lesion by reducing profibrotic key cytokines in dermatosis	[71]

Dissolvable MNs have gained considerable attention, because of excellent biocompatibility, high drug-loading capacity and without post-application removal. With “Poke and Release” mechanism, dissolvable MNs penetrate the stratum corneum and degrade in skin to release drugs in situ. This transient disruption of the epidermal barrier reseals within a short time, minimizing infection risks [61,62]. Thereby statistical analyses indicate that dissolvable MNs account for the majority of applications in TCM-MNs (Table 2). Further, stimuli-responsive MNs is an improvement over dissolvable MNs. Diseased tissues are often characterized by a hostile microenvironment for drug delivery, comprising hypoxia, low pH, high cytokine concentrations, and so forth [[63], [64], [65]]. Particularly, tumor tissues are well-known for acidic and hypoxic microenvironment [66]. MNs have introduced stimuli-responsive materials that exploit environmental condition to trigger controlled release [67]. The systems protect the specificity and stability of TCM [[68], [69], [70]]. Song et al. engineered a dual-responsive MNs for light-triggered and pH-triggered sequential release in scleroderma therapy [71]. Paeoniflorin (Pae) in MNs first released by light trigger and created a slightly acidic microenvironment for another drug TP release. The combined anti-inflammatory and immunomodulatory effects were finally implemented. Bi et al. designed a H₂O₂-responsive gel-based MNs containing methotrexate (MTX) and epigallocatechin gallate (EGCG) for psoriasis [67]. It achieved dual-mode drug release kinetics for sustainably released EGCG in an H₂O₂-responsive way to extended skin retention. Only few TCM-MNs employ stimuli-responsive designs currently, may due to the complicacy of TCM and the early stage of research technique [72]. Continued exploration of MNs types and strategies is warranted to fully realize the potential of TCM-MNs.

3.2. Appropriate materials for TCM-MNs

Dissolvable MNs is the most common type of TCM-MNs. TCM is characterized by multi-component interactions and diverse physicochemical properties. It is necessary to select materials for TCM-MNs to ensure efficient loading, stability and performance. Polymers such as hyaluronic acid (HA), polyvinylpyrrolidone (PVP), and polyvinyl alcohol (PVA) are widely employed owing to their hydrophilicity, biodegradability and biocompatibility. MNs are often fabricated from blends of two or more polymers to optimize mechanical strength and flexibility. The combination of hydroxypropyl methylcellulose (HPMC) and PVA can provide both rapid skin penetration and sustained release. These polymers also show enough drug-loading efficiency and preserve activity of most TCM ingredients [[81], [82], [83]].

Many TCM ingredients exhibit poor water solubility, so it is essential to use non-hydrophilic excipients to ensure solubility and effective loading. Materials such as chitosan and polydimethylsiloxane (PDMS) not only improve encapsulation efficiency but also slow in vivo release to extend the therapeutic window. Cui et al. developed berberine (BBR)-loaded chitosan MNs arrays (BR-CS MNAs) to deliver the ingredients into epidermis and dermis. BR-CS MNAs degraded within approximately 480 min and achieved a time-dependent release and superior permeability compared to equivalent MNs made by HA [73].

TCM volatile oils are water-insoluble, volatile and prone to oxidation. Volatile oils are unsuitable for incorporation into conventional HA or PVP. A notable example is elemene (ELE), an antitumor agent with poor solubility and high volatility. PDMS with waterproof properties, high elasticity and gas permeability more suits the transdermal delivery of ELE [74]. Small molecules (<500 Da) with moderate lipophilicity can freely cross the skin barrier, which is not good news for TCM peptides a kind of water-soluble macromolecules. Hydrophilic polymers with sufficient toughness and brittleness are needed [84,85]. Xu et al. optimized a matrix containing 20% PVP and 20% HA to fabricate MNs for Chinese cobra neurotoxin. The MNs exhibited a tip force of 39.88 ± 3.09 N and achieved a cumulative penetration efficiency of 97.99% ± 2.80% [85]. By contrast, the neurotoxin in aqueous solution barely permeated the skin. TCM polysaccharides are natural high-molecular-weight polymers. Owing to the compatibility and functional versatility, polysaccharides can combine with other excipients to prepare MNs and serve as therapeutic agents. So, some herb sap with high amount of polysaccharide even directly cure to form MNs. This specific application is discussed in the following sections.

When it comes to complex TCM extraction or prescriptions, the complexity of materials also correspondingly increases. Accordingly, it is particularly important to choose materials with different properties and adjust the appropriate proportions. The specific situation should be analyzed case by case.

4. Forms of TCM-MNs and combination therapy

4.1. TCM-MNs loaded with active ingredients

Advanced pharmacological researches have led to a deeper understanding of the biological activities of TCM ingredients. TCM-MNs with single active ingredients are commonly prepared by dissolving both ingredient and matrix into micromolds to replicate the desired MNs structure [86]. Resveratrol (RVT), a representative TCM polyphenol is always limited by poor solubility and bioavailability in application [87]. While RVT delivered by MNs resulted in more than three folds increase in intradermal accumulation compared to topical gel formulations [88]. Owing to the simple and reproducible formulation, MNs delivering single ingredients facilitates both improved therapeutic utilization and investigations.

Nonetheless, single component is not sufficient enough to some multifactorial diseases. TCM-MNs containing two or more ingredients have indicated synergies [89]. Khairani et al. constructed MNs with curcumin and piperine (NPs-CP-DMN) as antimalaria [90]. Curcumin promotes the generation of intracellular reactive oxygen species (ROS) to damage mitochondrial and nuclear DNA in Plasmodium [91]. Piperine has been proved to potentiate the bioavailability of curcumin and disrupt DNA synthesis in the parasite [92]. The NPs-CP-DMN leveraged both oxidative stress induction of curcumin and interference on DNA replication of piperine, for a synergistic inhibition of Plasmodium viability [90]. Such combinatorial approach of TCM-MNs opens the new avenue for precision therapy and synergistic interactions among multiple phytochemicals.

4.2. TCM-MNs loaded with extraction or prescriptions

Based on the traditional therapeutic philosophy of TCM, whole herbal extractions and classical TCM prescriptions still play a central role in clinical practice. Unlike synthetic pharmaceuticals, TCM often involve a nature mixture of bioactive compounds to work synergistically. This principle is summarized in “Jun-Chen-Zuo-Shi” theory, wherein different herbs are classified into roles, monarch, minister, assistant and guide, to reinforce mutual regulation and cooperation [[93], [94], [95]]. Despite the pharmacological value, extraction or prescriptions are facing with poor stability, short biological half-life and limited patient compliance [96].

MNs have achieved the transdermal delivery of complex TCM. Aiming at Atractylodes macrocephala Rhizoma aqueous extract, MNs with 6.0% PVA, 15.5% HA and 16.0% PVPK30 (AM-DMN) support to 0.3−2.5% drug loading range and 96% puncture rate, validating the potential of TCM extraction-MNs. AM-DMN kept extract stability and regulated intestinal flora imbalance for mammary gland hyperplasia [97]. Yunnan Baiyao is a classical TCM prescription famous for potent hemostatic activity [98]. MNs was prepared by gelatin methacrylate and Bletilla-derived polysaccharides for Yunnan Baiyao (BY-EGF@MNs). Compared with conventional gauze, BY-EGF@MNs achieved rapider dissolution (within 6 min) and deeper skin penetration to prompt coagulation cascade reaction (Fig. 1A) [99]. During the preparation process, it is necessary to guarantee loading capacity, stability and uniformity of TCM in MNs. Pre-processes like purification, concentration and lyophilization are often employed to convert extracts into dry powders for precise formulation [100]. Tang et al. reported a TCM-MNs composed of lyophilized extracts from Sanguis draconis (SD) and Salvia miltiorrhiza (SMR) (MN-SD@SMR) for diabetic wound healing (Fig. 1B) [101]. SD inhibited blood glucose and SMR improved blood flow velocity and microcirculation in wound area. It underscored the potential of MNs for processed TCM extracts.

Fig. 1.

(A) Yunnan Baiyao-loaded multifunctional MNs for rapid hemostasis and cutaneous wound healing. Reproduced with permission from [99], Copyright 2023, Spring Nature; (B) Soluble PVP-based MNs loaded with SD and SMR for treatment of diabetic wound healing. Reproduced with permission from [101], Copyright 2024, Wiley-Blackwell.

Current research predominantly focuses on TCM-MNs with one or a few active ingredients. TCM extractions and prescriptions meet decoction, filtration, precipitation, evaporation, drying and other technical challenges. However, TCM extract-MNs have a broader pharmacodynamic profile and are consistent with traditional TCM holism. TCM-MNs optimization on extractions and prescriptions deserves more attention in future studies. It is an ideal hope to preserve the integrative and systemic treatment philosophy of TCM, when exerting TCM-MNs efficacy.

4.3. Unification of medicines and excipients

There is a unique rooted concept in TCM modernization called “unification of medicines and excipients”. TCM used in formulation not only serve as auxiliary materials, but also contribute therapeutic benefits, which is not possessed by chemical and biological drugs. “Unification of medicines and excipients” can be originated from ancient TCM works. In “Shanghan Lun”, animal gelatin juice, plant sap and starch paste were used as excipients in pills and ointments, and helped to exert drug efficacy and ensure stability [102]. In modern formulations, there are saponins in liposome, volatile oil in nanoemulsion, and so on. Saponins, with a similar structure to cholesterol, are often used to replace cholesterol in liposome synthesis. Ginsenoside Rg3-based liposomes demonstrate improved tumor targeting and antitumor efficacy compared with conventional cholesterol liposomes [103].

“Unification of medicines and excipients” is also increasingly used in MNs. TCM contains large amounts of polysaccharides with rich pharmacological activity. Natural polysaccharides are commonly used as MNs matrices due to the favorable physicochemical characteristics and biocompatibility [[104], [105], [106], [107]]. Bletilla striata polysaccharide (BSP) is one of the most widely utilized TCM polymers in MNs. As matrix, BSP is biodegradable, non-toxic, and non-irritating. And BSP has effects in hemostasis, antimicrobial effects, wound healing and antitumor [70,108,109]. Zhou et al. developed BSP-based dissolvable MNs (BMNs) with excellent mechanical strength, biostability and safety [110]. Unlike HA or PVA MNs, BMNs exhibited lower hygroscopicity to prevent premature water absorption and preserved structural integrity. When used for transdermal vaccine delivery, anti-inflammatory properties of BSP mitigated the microtrauma caused by skin penetration. Zhang et al. fabricated BSP and HA MNs to deliver EGCG. EGCG@BSP/HA MNs exhibited better antibacterial activity than traditional antibiotics, and without inducing drug resistance [111].

Emerging researched identify additional TCM polysaccharides as viable MN matrices. Wang et al. utilized Panax notoginseng polysaccharide (PNPS) to fabricate dissolvable MNs with robust mechanical properties and efficient skin penetration. PNPS also acted as an immunoadjuvant to target skin-resident dendritic cells (DCs) and stimulate immune responses [112]. Peach gum polysaccharide (GP) has also been investigated as a biodegradable alternative to HA. GP-based MNs exhibited superior mechanical strength to enhance transdermal delivery for multifunctional nanoparticles in rheumatoid arthritis (RA) treatment (Fig. 2A) [113]. When rich in polysaccharides and pectin, TCM extractions can directly function as MNs matrix [114]. Chi et al. introduced a novel TCM-MNs (CHMN) prepared from the sap of Premna microphylla and Centella asiatica [115]. The extractions were obtained by a traditional kneading method and solidified by plant ash to form CHMN. Finally, the CHMN represented a significant wound healing efficacy in rat (Fig. 2B).

Fig. 2.

(A) Nanoparticles integrated into dissolving MNs based on peach gum polysaccharide to enhance local treatment of arthritis. Reproduced with permission from [113], Copyright 2022, Elsevier B.V.; (B) CHMN integrating pure extracts of Premna microphylla and Centella asiatica for wound healing. Reproduced with permission from [115], Copyright 2021, Elsevier B.V.

Overall, “unification of medicines and excipients” in TCM-MNs represents a promising paradigm for pharmaceutical innovation. The approach not only reduce synthetic additives, but also increase drug loading of TCM, offering a powerful strategy for TDDS within TCM principles.

4.4. TCM-MNs loaded with TCM nanoparticles

Nanoparticle-based delivery systems are well known to enhance the solubility, stability, targeting precision and controlled release of drugs. Widely studied platforms include liposomes, nanoemulsions, polymeric carriers, metal-organic frameworks (MOFs), responsive nanoparticles and even nature nanovesicles [116,117]. Encapsulating TCM ingredients within nanoparticles not only improves solubility and stability but also facilitates the incorporation into MNs [[118], [119], [120], [121]]. Correspondingly, the structural capacity of MNs promotes better penetration for TCM nanoparticles. Rutin, a TCM-derived flavonol glycoside, is troubled by water insoluble and highly sensitivity to air, heat and light [122]. Li et al. formulated rutin into liposome-loaded dissolvable MNs.

Liposomes easily made by lecithin and cholesterol improved rutin’s solubility and stability [123]. Incorporation into MNs (MP-LR) deliver targeted to adipose tissue. MP-LR significantly enhanced anti-obesity compared to oral or intravenous administration. Stimuli-responsive nanoparticles, triggered by internal stimuli like pH and ROS, or external cues like temperature, ultrasound and light, provide controlled release kinetics and limit off-target toxicity [[124], [125], [126]]. Liu et al. constructed a ROS-responsive nanoparticle system (FTL@SIN) to encapsulate the anti-rheumatic agent sinomenine. MNs fabricated from fucoidan finished the skin penetration of FTL@SIN. Sinomenine in FTL@SIN was released and activated by ROS in inflamed tissue to treat RA (Fig. 3A) [127]. Some nanocarriers possess intrinsic pharmacological activity, which can be integrated within MNs for multifunctional therapeutic design. Yang et al. developed a composite system (PDA/RLipo@BerMN) that incorporated BBR-loaded ginsenoside Rg3 liposomes, polydopamine (PDA) and HA-MNs, in which each component contributed a specific function [128]. The HA-MNs provided dermal penetration and controlled release. BBR delivered antimicrobial effects and ginsenoside Rg3 supported tissue regeneration. Last, PDA offered anti-inflammatory and antioxidant properties. The synergistic system effectively accelerated the wound healing (Fig. 3B).

Fig. 3.

(A) Inflammatory macrophage reprogramming strategy of fucoidan MNs-mediated ROS-responsive polymers for RA. Reproduced with permission from [127], Copyright 2024, Elsevier B.V.; (B) Multifunctional composite MNs based on “one stone, three birds” strategy for promoting the healing of infectious wounds. Reproduced with permission from [128], Copyright 2024, Elsevier B.V.

Beyond synthetic nanoparticles, endogenous nanoparticles such as exosomes have also emerged as potential delivery vehicles [129,130]. Based on the anti-inflammatory effects of Portulaca oleracea L.-derived nanovesicles (PDNV) by modulating macrophage M1/M2 polarization, a dissolvable MNs for deeper PDNV transdermal permeation was made, which illustrated the efficient utilization of plant exosomes in atopic dermatitis (AD) treatment [131]. The combination of MNs and TCM nanoparticles constitutes a dynamic delivery platform that reduces systemic exposure and optimizes localized drug bioavailability. The integration expands the therapeutic versatility of TCM ingredients, representing an exciting frontier for TCM-based interventions [132,133].

4.5. Combination therapy with TCM-MNs

Additionally, TCM-MNs provide a synergistic platform with other therapeutic modalities. Acupoint stimulation has long been utilized in TCM to treat a wide range of diseases. For instance, Baihui (GV20) stimulation is known to improve cognitive function in Alzheimer’s disease, and Zusanli (ST36) activation has anti-inflammatory benefits in RA [134]. TCM-MNs can precisely deliver at specific acupoints, aligning well with the principles of acupuncture [135]. Both mechanical and pharmacological stimulation of MNs potentially enhanced acupoint efficacy [136,137]. A flexible dissolvable MNs was developed containing seven tranquilizing TCM herbs extractions for sleep modulation. Applied to the Anmian (Extra) and Yintang (GV24) acupoints, the MNs increased high-frequency brain wave activity to effectuate neurologically targeted interventions [138].

TCM-MNs are also co-formulated with chemical drug to exploit complementary mechanisms. Lin et al. designed a dual-loaded MNs containing rapamycin and EGCG. Rapamycin promoted the transition of hair follicles from the telogen to anagen phase, and EGCG supported hair follicle proliferation through antioxidant and anagen-promoting effects. The combination therapy of MNs significantly exceeded either agent alone in hair regrowth [139]. TCM-MNs also successfully integrate with phototherapy, thermotherapy and other adjunct treatments. Zhang et al. developed a wireless near-infrared (NIR)-powered MNs (NIR-LED-NG-R1-MN) for controlled release of notoginsenoside R1 in wound healing. NIR light stimulation provided both thermal and photobiological regulation for synergistic wound healing [140].

In summary, MNs serve as a versatile delivery platform for different form of TCM. Some TCM ingredients can function as both MNs matrices and rich pharmacological activities. Moreover, TCM-MNs can be combined with acupuncture, chemotherapy, phototherapy and other approaches synergistically. The goal of TCM-MNs across different modalities is to enhance the therapeutic potential of TCM and broaden the clinical application in modern medicine (Fig. 4).

Fig. 4.

Different form of TCM-MNs and the combination therapy with TCM-MNs.

5. Application of TCM-MNs in transdermal therapy

5.1. Skin diseases

5.1.1. Wound healing

Skin integrity impaired by mechanical injuries [141], diabetes [142] and malignancies [143], always lead to wound infection and significant morbidity [144,145]. TCM have been demonstrated promising potential in promoting wound healing with minimal adverse effects [146,147]. Bioactive TCM compounds, like polysaccharides, flavonoids [148], polyphenols [149] and alkaloids [150], have shown different degrees in reducing oxidative stress and inflammation levels, promoting angiogenesis, and enhancing cellular proliferation [[151], [152], [153]].

Wounds present unique delivery challenges, depended on variability of tissue depth, the presence of wound exudate and bacterial colonization. Consequently, TCM-MNs offer an effective way with enough mechanical strength and localized therapeutic agents release [[154], [155], [156]]. Luan et al. developed a hydrogel-based MNs co-loaded with BBR and Aloe vera extract (BBRMN). BBRMN showed antibacterial and anti-inflammatory effects in early-stage and promoted fibroblast proliferation to support the entire wound healing cascade (Fig. 5) [60]. A multifunctional dissolvable MNs embedded with MOF were constructed to co-deliver curcumin and magnesium ions. The MNs were able to achieve site-specific release of both agents. The combined effects led to better healing of skin ulcers than traditional commercial triamcinolone acetonide oral ointment [157]. Collectively, the integration of bioactive herbal compounds with advanced MNs delivery platforms accelerated wound healing and improve patient outcomes in dermatological care, which demonstrated the platform’s utility in treating chronic wounds.

Fig. 5.

(A) Schematic diagram and (B) application of BBR-loaded MNs; (C) Optical photography and SEM images of MNs; (D) Representative images of the wounds with different treatments. Reproduced with permission from [60], Copyright 2024 Wiley-VCH GmbH.

5.1.2. Hypertrophic scar

Hypertrophic scars are common dermatological conditions characterized by abnormal fibroblast proliferation and excessive collagen deposition following trauma or skin infections [158,159]. Conventional therapies like surgical excision, radiotherapy and pharmacological interventions, are frequently associated with limited efficacy, high recurrence rates and notable side effects [160]. Scar tissues are thicker and harder than healthy skin. TCM-MNs can penetrate the fibrotic barrier, which is a promising choice for hypertrophic scars management [29,161].

Quercetin (QUE) is a common flavonoid with anti-fibrotic and antioxidant properties. Wu et al. developed a dissolvable BSP MNs and incorporated a diphenyl carbonate cross-linked cyclodextrin MOF (CDF) as a carrier for QUE (BSP-MNs-QUE@HSF/CDF). BSP-MNs-QUE@HSF/CDF downregulated Wnt/β-catenin and JAK2/STAT3 signaling pathways and suppressed collagen I and III expression to attenuate scar formation [162]. BSP also acted as “unification of medicines and excipients” in BSP-MNs-QUE@HSF/CDF. Protocatechuic aldehyde (PA) has been reported to play a role in key processes of hypertrophic scar formation. When incorporated into HA-based MNs, MNs exhibited sufficient mechanical strength to penetrate scar tissue and PA directly reached the pathological site to induce fibroblast apoptosis, reduce collagen production and inhibit angiogenesis [163]. Dual-drug strategies further show synergistic treatment. A sequential release system combining gallic acid (GA) and QUE was designed for preventing scar progression. The MNs achieved stage-specific modulation, with GA released early to suppress fibroblast proliferation and QUE released later to mitigate ROS accumulation (Fig. 6) [78]. In a word, it is obvious that TCM-MNs have therapeutic potential in managing hypertrophic scars with targeting, synergy and innovative drug release.

Fig. 6.

(A) Illustration of quercetin-loaded amphiphilic gelatin nanocarrier, and the prevention of keloid scars by modulating heterogeneous gelatin-structured composite MNs; (B) Light microscope photograph of MNs with various loading conditions; (C) H&E-stained skin sections after different treatment. Reproduced with permission from [78], Copyright 2022, MDPI.

5.1.3. Psoriasis

Psoriasis is a chronic autoimmune skin disorder marked by excessive keratinocyte proliferation, epidermal thickening and systemic inflammation [164,165]. Conventional therapies represented by apremilast, MTX and adalimumab always fail to achieve complete remission with long-use and are accompanied by adverse effects [166]. Conversely, TCM is a safer way offering high patient tolerance and a lower incidence of systemic toxicity [167].

The therapeutic potential of TCM ingredients in psoriasis mainly performed as inhibiting pro-inflammatory signaling cascades and reducing keratinocyte hyperproliferation [167,168]. Coupled with the skin-penetrating capabilities of MNs, bioactive TCM compounds can be deeply delivered to psoriatic lesions. For instance, ELE, a sesquiterpene with immunosuppressive properties, has been shown to induce apoptosis in psoriatic keratinocytes and suppress M1 macrophage-derived inflammatory cytokines. ELE-loaded HA MNs (HA-ELE-MNs) was developed to enhance local delivery and targeted multiple inflammatory pathways in psoriatic mouse models [169]. When encapsulated in a liposome-based MNs (Rg3-MNs), ginsenoside Rg3 exerted superior retention and less skin irritation compared to free Rg3 or Rg3-liposomes. The therapeutic mechanism was attributed to inhibition of the STAT3/p-STAT3 signal and downregulation of cytokines (IL-17, IL-23 and TNF-α) [170].

MTX as a first-line drug for psoriasis is limited by systemic toxicity for long-term use [171,172]. A natural polyphenol phloretin with antipsoriatic activity was incorporated into MNs to provide sustained drug release. The MNs showed equivalent therapeutic efficacy to MTX while offering a better safety profile for long-term management [173]. Furthermore, MNs present a novel option to combine TCM and conventional drugs. A flavonoid puerarin (Pue) was integrated with photo-crosslinked gelatin methacryloyl (GelMA) and co-loaded with MTX (Pue/GelMA-HMNs). This system exceeded oral and subcutaneous MTX delivery in alleviating psoriasis symptoms and cytokine levels. Notably, Pue enhanced MTX efficacy synergistically and mitigated MTX side effects, offering a balanced treatment (Fig. 7) [174]. It was supported that TCM-MNs as an innovative and patient-friendly strategy for effective and safer psoriasis therapies by the localized and controlled delivery of anti-inflammatory and immunomodulatory TCM ingredients.

Fig. 7.

(A) Illustration of MTX-loaded Pue/GelMA HMNs for psoriasis treatment; (B) Microscopy images and SEM images of Pue/GelMA HMNs at different magnifications; (C) Images (bottom) of histology sections of porcine skin after insertion by fluorescein-loaded Pue/GelMA HMNs; (D) IL-6 and TNF-α level of psoriasis mice with different treatments; (E) Images of mice dorsal skins with various treatment and heatmap of PASI score (total) of each mouse. Reproduced with permission from [174], Copyright 2025, Elsevier B.V.

5.1.4. Atopic dermatitis (AD)

AD is a chronic autoimmune skin condition characterized by xerosis (dry skin), erosions, edema, bleeding and intense erythema [175]. But it is still unresolved that corticosteroids as the first-line therapy often cause severe adverse effects and patient response variability under long-term usage [81,33]. In contrast, bioactive TCM ingredients, not confined to flavonoids, phenols and terpenoids, show significant potential in alleviating AD with a safer profile [[176], [177], [178]]. TCM-MNs improve patient compliance and achieve better anti-inflammatory, antioxidant and anti-allergy in AD treatment [179].

Matrine (MAT) is an alkaloid extracted from Sophora flavescens and is good at dealing with pruritus, inflammation, and allergic skin diseases [180]. Wang et al. designed dissolvable MNs loaded with MAT (MAT-DMNs) to show sustained release kinetics and >70% cumulative penetration rate. MAT-DMNs significantly reduced epidermal thickening and mast cell infiltration in murine AD models. MAT-DMNs also decreased levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) to ultimately lower lesion scores [181]. EGCG has also been formulated into MNs (EGCG/AA-loaded γ-PGA MNs) for AD treatment. EGCG/AA-loaded γ-PGA MNs provided a patient-friendly delivery to successfully mitigate AD symptoms by offering antioxidant protection (Fig. 8) [77]. Therefore, TCM-MNs represent a promising TDDS to conventional AD therapy, combining the holistic benefits of TCM with the technological advantages of MNs [182].

Fig. 8.

(A) Illustration of using EGCG/AA-loaded γ-PGA MNs for ameliorating AD-like symptoms in mice; (B) Photographs after EGCG/AA-loaded γ-PGA MNs insertion and removal from the skin. (C) Representative images of dorsal skin lesions captured at weeks 0, 2 and 4; (D) H&E (a) or toluidine blue-stained (b) skin sections of Nc/Nga mice at week 4. Reproduced with permission from [77] Copyright 2021, Acta Materialia Inc. Published by Elsevier Ltd.

5.2. Hair-related disorders

Hair is a key component of the integumentary system. It plays not only a protective role but also serves aesthetic and psychosocial functions. Disorders such as alopecia and hair graying become more prevalent and difficult to manage, which often cause the psychological impact and quality of life [[183], [184], [185]]. Current food and drug administration (FDA)-approved drugs, like minoxidil and ruxolitinib, are associated with high costs, limited efficacy and undesirable side effects [186]. TCM have historical efficacy in treating hair-related diseases, with examples widely known including Zingiber officinale (ginger), Polygonum multiflorum and Platycodon grandiflorus leaves, as well as some active ingredients like ginsenosides and baicalin [[187], [188], [189], [190]]. However, clinical efficacy is limited by poor skin penetration and follicular targeting. MNs overcome the barriers and enhance patient adherence [191].

Alopecia is the most prevalent class of hair loss disorders, represented by androgenic and seborrheic forms. TCM-MNs as drug carriers can stimulate hair regrowth via controlled mechanical disruption on skin simultaneously [192]. A dissolvable MNs with a flexible backing delivered cedrol, a sesquiterpene from Platycladus orientalis, directly to hair follicles with improved local drug concentration and promoted robust hair regeneration [193]. Yang et al. developed a dissolvable MNs with HA and BSP to encapsulate Rg3-loaded liposomes [194]. BSP enhanced strength and biocompatibility of MNs for follicular delivery. And MNs achieved superior hair regrowth through activating Wnt/β-catenin, compared with minoxidil. A QUE-loaded copper/zinc dual-doped mesoporous silica nanoparticles embedded in dissolvable MNs to yield synergistic regeneration. The flavonoid-metal chelates were released to target multiple pathways of androgenic alopecia, referring to inhibit dihydrotestosterone (DHT), reduce inflammation, promote angiogenesis and also activate follicle stem cells [195]. Further, MNs loading with curcumin and zinc MOFs (ZnMOFs) demonstrated efficacy in both wound healing and hair regrowth. The MNs addressed multiple etiologies of hair loss including zinc deficiency, oxidative stress and impaired cell proliferation [196].

TCM-MNs also present a promising avenue for hair graying. Psoralea corylifolia extract (PE) showed clinical efficacy in reversing depigmentation via topical or oral administration [197]. Hu et al. designed a dissolvable MNs (PE-MNs) with a flexible base to accommodate scalp curvature. PE-MNs ensured precise follicular delivery and avoid systemic toxicity, successfully to inhibit hair graying progression (Fig. 9) [198].

Fig. 9.

(A) Diagram of the preparation process of PE-MNs; (B) Characterization of PE-MNs; (C) Photographs of the treated skin area, and the melanin contents of C57BL/6 mice hair shafts in each group; (D) Images of new hairs in the depilated areas of each group, and representative images of Fontana-Masson staining of dorsal skin sections. Reproduced with permission from [198], Copyright 2024, Elsevier B.V.

5.3. Rheumatoid arthritis (RA)

RA is a systemic autoimmune disease that can compromise joint function and impair patient quality of life significantly. The pathophysiology of RA involves persistent synovial inflammation, dysregulated immune responses, and pathological angiogenesis [199]. Although, disease-modifying antirheumatic drugs (DMARDs) are the cornerstone of conventional RA treatment, the long-term use of DMARDs often causes serious adverse effects, commonly including hepatotoxicity, nephrotoxicity and increased infection risk [200].

Recent years, TCM have attracted attention as candidate therapeutic method for RA. The immunomodulatory and anti-inflammatory properties of TCM underpin research interest [201]. Tripterygium wilfordii (TW) is widely used to treat autoimmune conditions, shown clinical efficacy superior to some DMARDs [202]. But the therapeutic potential of TW-derived compounds is limited by systemic toxicity and poor bioavailability. TP, one of extraction from TW, has potent anti-inflammatory and immunosuppressive effects and also carries significant systemic toxicity. The way to encapsulate TP in HA-MNs delivered TP to inflamed joints directly and reduced inflammation levels with less off-target organ damage at the same time [50]. The localized delivery of TCM-MNs enhances both efficacy and safety, laying the foundation for clinical translation of TCM-MNs in RA treatment [203,204]. BBR and sinomenine are also well-known for their bioactivities on RA. Hua et al. developed a ROS-responsive micellar formulation co-loaded with BBR and sinomenine (B/S-TM), which was embedded in carboxymethyl cellulose-based MNs (B/S-TM@MN) [79]. B/S-TM@MN dissolved and allowed B/S-TM accumulated in inflamed joints via the ELVIS effect after skin penetration. Then high ROS in joints triggered controlled release of BBR and sinomenine to repolarize macrophages, suppress cytokines, inhibit endothelial migration and reduce neovascularization [79]. Another TCM compound hypericin (HYP), a natural molecule derived from Hypericum perforatum exhibits both anti-inflammatory and photodynamic properties, also with hepatotoxic risk [205,206]. HYP was encapsulated in emulsomes and delivered via AdminPen™ metallic hollow MNs to solve the toxicity issues. Targeted transdermal dosing, combined with photodynamic stimulation, maximized intra-articular activity for RA treatment (Fig. 10) [207].

Fig. 10.

(A) Illustration of HYP EMLs by MNs combined with PDT; (B) Schematic representation and further characterization techniques; (C) Photomicrograph of joint in different groups; (D) Joint morphology of different groups. Reproduced with permission from [207], Copyright 2024, Elsevier B.V.

5.4. Tumor

Tumor is a disease with high morbidity and mortality worldwide. Despite of surgery, chemotherapy and immunotherapy, clinical outcomes are still unsatisfactory. TCM has attracted more attention for multifunction in tumor management, showing the inhibition of tumor growth and metastasis, reversal of multidrug resistance and modulation of the immune microenvironment [[208], [209], [210], [211]]. For instance, curcumin can reduce pro-inflammatory cytokine production and tumor progression through inhibiting the NF-κB and STAT3 signaling pathways [[212], [213], [214]]. Ginsenoside Rg3 has been proved to promote apoptosis, suppress angiogenesis, and modulate immune responses in tumor microenvironment. Rg3 is also the principal active ingredient in ShenYi Capsule, a TCM formulation for clinical tumor therapy in China [215]. MNs have shown great value in tumor vaccines delivery and immunotherapy with minimally invasive and patient-friendly alternative to repeated injections. MNs are expected to offer a favorable way for TCM to attain targeted tumor delivery [54,216]. Currently, TCM-MNs were mainly applied in superficial tumors.

Effective penetration on tumor improves local concentration and precision to minimize systemic exposure [54,217,218]. Yi et al. developed a methacryloyl gelatin-based MNs encapsulating Rg3, which promoted intratumoral Rg3 release with favorable kinetics, and significantly enhanced antitumor efficacy via inducing apoptosis and inhibiting cell proliferation in ovarian tumors [219]. Similarly, RVT, as a polyphenolic compound with antitumor potential, was formulated into nanostructured lipid carriers (RVT-NLCs) and then administered by MNs in breast cancer treatment. Compared to oral delivery, RVT-NLCs delivered by MNs demonstrated enhanced tissue penetration and improved drug accumulation in tumor sites to achieve greater therapeutic effects, highlighting the value of MNs-mediated delivery [220]. TCM-MNs provide a viable and innovative strategy for future tumor treatment, aiming to enhancing the efficacy, targeting, and patient compliance in tumor therapy, particularly for superficial tumor.

5.5. Others

With research advancement and clinical demand, TCM-MNs create new opportunities for TCM application and therapeutic efficacy. Cinnamon oil (CIO), which has the activity of anti-inflammatory and analgesia, was encapsulated in nanocapsules and then loaded into HA-MNs (HAMNs-CIO@NCs) to treat dysmenorrhea. HAMNs-CIO@NCs improved stability, reduced odor, and lowered skin irritation to enhance compliance. The MNs also reduced the uterine PGF2α/PGE2 ratio and alleviated primary dysmenorrhea [221]. For the same active ingredient, MNs provide the possibility of application in different diseases and potentiate efficacy. Prabhu A et al. loaded curcumin into MNs for Parkinson’s disease. It was more effective than subcutaneous injection and remained non-irritating [222]. Curcumin also showed potent anti-inflammatory effects. MNs delivery helped overcome ocular barriers and reduced intraocular inflammation [223].

There are diverse active ingredients in TCM, with multiple pharmacological activities and low toxicity. As a drug delivery system, MNs can improve the effective delivery of components, making the combination of TCM and MNs an important contribution in the treatment of various diseases. It is worth further research and development in TCM-MNs to provide safer and more efficient treatment plans for patients in the future.

6. Challenges of TCM-MNs standardization

Research on TCM-MNs has advanced traditional medicine. Significant challenges remain before widespread adoption. There are no commercial TCM-MNs, owing to obstacles like high costs, manufacturing limits, and insufficient clinical validation. Require rigorous studies and standardized production are needed. Also, the cost-effective fabrication and tailored regulatory frameworks should be paid attention. The standardization on TCM has gained international organization for standardization (ISO) recognition, while uniform standards for TCM-MNs remains a major challenge. The chemical diversity of TCM ingredients further complicates industrial translation. It is critical for large-scale manufacturing to optimize formulas and quality control.

It is noteworthy that quality markers (Q-markers) have been proposed as key indicators for evaluating the overall quality of TCM formulations. Advanced techniques such as high performance liquid chromatography (HPLC), gas chromatography (GC) and liquid chromatography-mass spectrometry (LC-MS) are highly anticipated to quantify Q-markers for clarifying the interactions of ingredient-metabolite-gene-protein from TCM-MNs [224]. It is essential to ensure the uniformity, effectiveness, stability and reproducibility of TCM-MNs through reliable indicators. In parallel, artificial intelligence (AI) has emerged as a valuable tool for TCM modernization [225]. In industrial manufacturing, AI can help to integrate prescription ratios, equipment settings and material properties for optimizing processes, which is able to reduce trial costs and reach efficient scheme. AI tracks key components, links processes to quality outcomes, and elucidates TCM-MN pharmacology in vitro and in vivo, which helps to interpret complex formulations. Based on growing awareness on health and well-being, the potential application of TCM preparations becomes vast. It is pivotal to strengthen the standardization and normalization of TCM-MNs through advanced technologies, for driving both their industrial adoption and the broader modernization of TCM in the future.

7. Conclusion and prospection

It is widely recognized that TCM have diverse pharmacological activities and favorable safety profile. Conventional TCM administration ways with inefficient absorption often face with poor compliance and limited bioavailability. MNs offer a transformative approach for modernizing TCM delivery. Compared with traditional TDDS, MNs significantly enhance dermal penetration and achieve controlled release, which are able to maintain stable plasma concentrations and improve both efficacy and patient adherence. This review has highlighted the types and advantages of TCM-MNs and discussed TCM-MNs loading with herbal extracts, classical prescriptions, nanoparticles and even multifunctional matrices. Differ from chemical drug-based MNs, TCM-MNs uniquely integrate “unification of medicines and excipients”, reduce toxicity and enhance pharmacodynamic efficiency. The potential synergy with acupuncture and other treatment methods further highlights the benefits of TCM-MNs.

Despite these promising developments, several prospects and needs remain for the future clinical adoption. First, TCM-derived exosomes are a new form of TCM, representing a compelling opportunity for innovation. Exosome-loaded MNs derived from mesenchymal stem cells have already been studied and shown promise as bioactive, cell-free transdermal platforms. TCM herbs as sources of functional exosomes has been proved like ginseng exosomes and ginger exosomes, which shown good biological activity in antitumor and anti-inflammatory activity. But the integration of MNs with TCM-derived exosomes (TCM-exosomes-MNs) is rare and warrants more investigation. Future research should test pharmacological relevance, targeting capacity, and biomarker potential across diseases. Second, most TCM-MNs use dissolvable MNs. Functional diversification is needed to improve delivery and add capabilities. Hollow and hydrogel-forming MNs, and stimulus-responsive MNs, could greatly expand the therapeutic scope of TCM-MNs. Smart systems could enable programmable release, real-time response to cues, and multifunctional therapy. Therefore, new materials that load TCM and possess specific responsive functions should be developed. Third, widespread therapeutic use of TCM-MNs suggests potential in cosmetics. MNs have been applied in cosmetics since 2005. MNs have improved wrinkles, scars and fat reduction, among others. At present, TCM also sparks a craze in cosmetology owing to its anti-inflammatory, antioxidant, and antimicrobial activities, among others. It is therefore evident that TCM-MNs warrant further research and hold promise for future development in the cosmetics field.

In conclusion, while significant progress has been made, the development of TCM-MNs remains in an early stage. Continued interdisciplinary efforts are essential to refine their design, expand their functionality, and establish their clinical utility. With further innovation, TCM-MNs have the potential to transform the landscape of transdermal therapy and offer safe, effective, and patient-friendly alternatives for the treatment of both skin and systemic diseases.

CRediT authorship contribution statement

Lixia Chen: Writing – review & editing, Writing – original draft. Yihua Xu: Writing – review & editing. Shengfei Yang: Software, Conceptualization. Ninggang Chen: Investigation. Jianqing Gao: Project administration, Funding acquisition. Hangjuan Lin: Project administration, Funding acquisition.

Conflicts of interest

The authors declare that there is no conflicts of interest.