Infections caused by anaerobic bacteria are common in oxygen-poor regions. Their slow metabolism makes most antibiotics less effective. And the small-molecule nutrients produced by anaerobic fermentation create a favorable growth environment for other bacteria, leading to multi-species infections. Due to the low tolerance of anaerobic bacteria to reactive oxygen species (ROS), stimulation of endogenous ROS generation could be a promising way to kill anaerobic bacteria. In this work, we used an antimicrobial peptide (AMP) (sequence: WRKFRRFKFRW-NH2, WRK for short) that induces anaerobic bacteria to produce intracellular ROS to treat infections caused by Propionibacterium acnes (P. acnes), a typical anaerobic bacterium that is often commensal in the skin. This antibacterial mechanism avoids the development of drug resistance and does not rely on oxygen. WRK peptide demonstrated excellent antimicrobial performance against P. acnes, inhibiting free-floating bacteria at 4 µg mL−1 and destroying biofilms at 64 µg mL−1. AMP can be delivered to the dermis through microneedles and effectively inhibits the proliferation of P. acnes in the infected area. In a mouse model of back acne, we confirmed the therapeutic effect of this AMP microneedle on P. acnes infection in vivo. The antibacterial microneedle treatment significantly reduced inflammation, demonstrating superior therapeutic efficacy compared to commercial clindamycin gel.

The efficient management of infected skin wounds is severely limited by the thick bacterial biofilm within the lesion, the intractable stratum corneum barrier of the perilesional skin, and the high toxicities of potent antibiotics. Sparfloxacin (SPFX) was withdrawn from the market due to its severe systemic side effects and UV-induced phototoxicity, while its severe hydrophobicity causes localized crystalline cytotoxicity upon topical application. To safely rejuvenate this potent drug, an integrated transdermal system combining photoshielding, SPFX-loaded solid lipid nanoparticles (SPFX-SLNs) with dissolving microneedles (MNs) was developed. This study primarily focuses on the systematic screening, formulation development, and optimization of SPFX-SLNs via Box-Behnken Design-Response Surface Methodology (BBD-RSM). The optimized nanocarriers exhibited a uniform size (86.85 ± 1.89 nm) and a two-fold higher antibacterial potency against Escherichia coli (E. coli) than free SPFX. Mechanistically, the solid lipid core locked SPFX in a safe amorphous state to preclude crystal-induced irritation, while functioning as a physical photoshield against UV activation. By depositing the nanomedicine exclusively into infected dermis, the MN platform minimized systemic drug exposure. In a rat model of E. coli-infected biofilm wounds, the formulated SPFX-SLNs MNs achieved over 50% (58.44%) wound closure within 3 days and near-complete re-epithelialization by day 11, and a 98.61% final closure rate by day 14. Ultimately, this work establishes a comprehensive formulation development strategy for a safety-enhanced, biofilm-penetrable nanomedicine-MN hybrid that successfully repurposes a clinically restricted antibiotic for advanced wound regeneration.

The combination of microparticles (MPs) with dissolving microneedles (DMN) represents a promising transdermal approach for the sustained release of biomacromolecule drug. In this study, we developed a doublelayered microparticles-dissolving microneedle (MPs-DMN) system, which strategically concentrates PLGA MPs at the tip of the microneedle to achieve sustained release of peptide drugs through transdermal delivery. We selected exenatide (EXT) as a model peptide drug and established HPLC-UV and UPLC-MS methods for the quantitative analysis of the drug content of MPs-DMN and drug concentrations in plasma. Ultrasonication was utilized in the first step of the double emulsion solvent evaporation method to produce PLGA microparticles, achieving a high drug loading efficiency of 22.76 f 0.64 %, surpassing the commercial products. The EXT-loaded microparticles were then mixed with 10 % w/v sucrose solution to form the first layer of the microneedle, and the mixture of the base solution was added to form the double-layered dissolving microneedle. Microscopic analysis revealed that the MPs were predominantly concentrated in the upper 50 % of the microneedle body, resulting in an impressive drug delivery efficiency of 92.86 f 1.62 %. The MPs-DMN patch demonstrated the capability to 238.20 f 5.79 mu g of EXT within a compact area of 0.75 cm2, surpassing the capacities reported in existing research. The insertion and dissolution assessments exhibited rapid dissolution, maintaining the MPs as an effective drug reservoir within the skin. Pharmacokinetic assessments indicated that the long half-life (T1/2) of 466.4 f 12.2 h and high relative bioavailability of 89.71 % for MPs-DMN. Furthermore, pharmacodynamic studies indicated that the MPs-DMN effectively controlled blood glucose levels below 20 mmol/L in diabetic (db/ db) mouse for two weeks. These promising findings suggest that the MPs-DMN system could serve as a viable transdermal delivery method for the prolonged administration of peptide drugs.

Port-wine stain (PWS), a progressive congenital vascular malformation characterized by ectatic dermal capillaries, demonstrates age-dependent lesion expansion and chromatic intensification, resulting in significant psychosocial comorbidity. While systemic hematoporphyrin (HP) administration remains the clinical paradigm for photodynamic therapy (PDT), its therapeutic utility is severely constrained by non-targeted biodistribution. Pharmacokinetic analyses reveal prolonged dermal retention and suboptimal lesion accumulation, predisposing 42% of patients to phototoxic reactions. To address these limitations, this work creatively suggested a local targeted drug delivery method based on soluble microneedles in response to the difficulties mentioned above. The rational design of a molecular weight (MW) HA gradient system enabled the engineering of ternary nanocomposite microneedles with enhanced biomechanical integrity (0.49 N/needle) and superior HP loading capacity, which collectively facilitated spatiotemporally controlled transdermal delivery of hematoporphyrin with complete dissolution within 30 min. The release performance, skin permeability, and storage stability of hematoporphyrin dissolving microneedles (HP-DMNs) have all been demonstrated in vitro. This study applies soluble microneedle technology to the delivery of HP in PWS for the first time. It avoids the risk of systemic exposure through precise local administration. It uses the rapid dissolution properties of microneedles to achieve high concentration and rapid release of drugs in skin lesions. This study provides a new strategy for sustained intralesional release and rapid drug delivery treatment of PWS and provides novel ideas for the development of new formulations of HP and related photosensitizers.

Osteoporosis is one of the most common diseases affecting the elderly, particularly postmenopausal women. It significantly increases the risk of fractures, reduces quality of life, and adds to the medical burden. Traditional formulations, such as alfacalcidol (ALF) capsules and tablets, have limitations, including difficulties in swallowing and patient resistance to long-term medication use, highlighting the urgent need for a sustained-release ALF formulation. To address this, we developed a double-layered core-shell microneedle patch integrated with ALF-loaded microparticles for the long-acting treatment of osteoporosis. This system aims to reduce administration frequency and improve patient compliance. After application for just 5 min, the patch can be removed, leaving the microneedle tips embedded in the skin. The core-shell structure of the tip consists of a core made of ALF-loaded polylactic-co-glycolic acid (PLGA) microparticles and a shell composed of ethylcellulose (EC). This structure acts as a drug reservoir within the skin, enabling for sustained release of ALF over 14 days. Compared to commercially available ALF tablets which require daily administration, the long-acting ALF double-layered core-shell microneedle patch (ALF-DCSMN) delivers a lower systemic drug dose while demonstrating comparable or better efficacy in increasing bone mass and improving trabecular microstructure. Notably, ALF-DCSMN only requires semimonthly administration. Overall, these promising results suggest that the ALF-DCSMN is a safe, effective, and user-friendly transdermal formulation for the long-acting treatment of osteoporosis.

Diabetes mellitus (DM)-associated wounds, characterized by chronic bacterial infections and elevated glucose levels, present significant challenges to effective healing. To overcome these issues, a novel transdermal drug delivery system was developed, integrating microneedles (MNs) with biofilm-penetrating capability, the wound-healing properties of hyaluronic acid (HA), the antibacterial effects of silver nanoparticles (AgNPs), and the glucose-lowering action of insulin (Ins). Named HAMNs@AgNPs-Ins, this system demonstrated optimal morphological characteristics, robust mechanical strength, and 100 % skin penetration efficiency. It exhibited sustained antibacterial activity in vitro, ensured skin safety, and provided controlled, steady blood glucose reductions, achieving a 72.29 % reduction at 8 h, compared to the sharp decline seen with subcutaneous injection. Additionally, wound healing experiments showed a significant improvement in the healing rate of 89.66 ± 1.34 % in the HAMNs@AgNPs-Ins group, compared to 48.19 ± 9.03 % in the control group. These results underscore the potential of HAMNs@AgNPs-Ins as an effective treatment for DM-associated wounds.

Efficient and synchronized co-delivery of active pharmaceutical ingredients (APIs) from classical Traditional Chinese Medicine (TCM) formulae is crucial for exerting their synergistic therapeutic effects. However, constructing dual-drug-loaded systems capable of controllably delivering APIs with divergent polarities remains challenging due to differences in molecular weight and solubility among constituents. In this study, paeoniflorin (PAE) and glycyrrhizic acid (GLA)-active ingredients derived from the renowned TCM formula Shaoyao Gancao Decoction-were selected as model compounds. To address the co-loading and synchronized delivery of hydrophilic PAE and hydrophobic GLA, we developed a β-glycerophosphate disodium salt (β-GP)/hydroxypropyl cellulose (HPC) hydrogel. This hydrogel uniquely combined skin-triggered sol-gel transition with electrostatically enhanced solubility for GLA, and was subsequently fabricated into a microneedles (MNs) formulation. Confocal laser scanning microscopy confirmed uniform distribution of both drugs within the MNs, despite their contrasting polarities. In vitro transdermal studies revealed that the MNs significantly outperformed the hydrogel in terms of delivery efficiency. Release kinetics followed the Higuchi model, with cumulative release rates at 72 h reaching 38.84 ± 0.52 % for PAE and 44.26 ± 4.38 % for GLA, indicating synchronized release. This platform represents an innovative strategy for achieving the synchronized, efficient, and sustained delivery, holding significant promise for advancing the development of TCM formulations.

Periocular wrinkles are among the most prominent signs of facial skin aging, significantly impacting patients' self-confidence and quality of life. Current cosmetic products, such as eye masks and wrinkle-reducing creams, face limitations including nonspecific active ingredient delivery and poor percutaneous absorption, resulting in suboptimal therapeutic results. This study introduces a novel complex plant extract-loaded dissolving microneedle (CPE-DMN), incorporating three active components: panax notoginseng saponins (PNS), rhodioloside, and madecassoside, with strong antioxidant activity to anti-wrinkle function. The CPE-DMN demonstrates sufficient mechanical strength for skin penetration and complete dissolution within 10 min, enabling efficient delivery of active ingredients. In vitro assessments confirmed the system's biosafety and its ability to significantly upregulate the gene expression of col1a1a, col1a1b, and col1a2 in zebrafish, which related to the regeneration of type I collagen. Furthermore, a 56-day clinical trial involving 31 volunteers demonstrated the CPE-DMN's efficacy, showing reduction in wrinkle count and under-eye puffiness, along with improved skin elasticity and firmness. These findings collectively indicate that the CPE-DMN system represents a safe and effective clinical approach for addressing periocular wrinkles.

Skin pigmentation typically arises from the excessive secretion and accumulation of melanin, resulting in a darker complexion compared to normal skin. Currently, the local application of chemical drugs is a first-line strategy for pigmentation disorders, but the safety and efficacy of drugs still cannot meet clinical treatment needs. For long-term and safe medication, researchers have paid attention to natural products with higher biocompatibility. This article begins by examining the pathogenesis and treatment approaches of skin pigmentation diseases and summarizes the research progress and mechanism of natural products with lightening or whitening effects that are clinically common or experimentally proven. Moreover, we outline the novel formulations of natural products in treating pigmentation disorders, including liposomes, nanoparticles, microemulsions, microneedles, and tocosomes. Finally, the pharmacodynamic evaluation methods in the study of pigmentation disorder were first systematically analyzed. In brief, this review aims to collect natural products for skin pigmentation treatment and investigate their formulation design and efficacy evaluation to provide insights for the development of new products for this complex skin disease.

Peptide vaccines induce specific neutralizing antibodies and are effective in disease prevention and treatment. However, peptide antigens have a low immunogenicity and are unstable, requiring efficient vaccine carriers to enhance their immunogenicity. Here, we develop a tobacco mosaic virus (TMV)-based peptide vaccine for transdermal immunization using a tip-loaded dissolving microneedle (MN) patch. TMV is decorated with the model peptide antigen PEP3. The prepared TMV-PEP3 promotes dendritic cell maturation and induces dendritic cells to overexpress MHC II, costimulatory factors, and pro-inflammatory factors. By encapsulation of TMV-PEP3 in the tips of a trehalose MN, TMV-PEP3 can be delivered by MN and significantly promote local immune cell infiltration. In vivo studies show that both subcutaneous injection and MN administration of TMV-PEP3 increase the production of anti-PEP3 IgG antibodies and the harvested serum can induce complement-dependent cytotoxicity. This work provides a promising strategy for constructing efficient and health-care-friendly peptide vaccines.

Purpose: Transdermal Drug Delivery System (TDDS) offers a promising alternative for delivering poorly soluble drugs, challenged by the stratum corneum's barrier effect, which restricts the pool of drug candidates suitable for TDDS. This study aims to establish a delivery platform specifically for highly lipophilic drugs requiring high doses (log P > 5, dose > 10 mg/kg/d), to improve their intradermal delivery and enhance solubility. Methods: Cannabidiol (CBD, log P = 5.91) served as the model drug. A CBD nanosuspension (CBD-NS) was prepared using a bottom-up method. The particle size, polydispersity index (PDI), zeta potential, and concentration of the CBD-NS were characterized. Subsequently, CBD-NS was incorporated into dissolving microneedles (DMNs) through a one-step manufacturing process. The intradermal dissolution abilities, physicochemical properties, mechanical strength, insertion depth, and release behavior of the DMNs were evaluated. Sprague-Dawley (SD) rats were utilized to assess the efficacy of the DMN patch in treating knee synovitis and to analyze its skin permeation kinetics and pharmacokinetic performance. Results: The CBD-NS, stabilized with Tween 80, exhibited a particle size of 166.83 +/- 3.33 nm, a PDI of 0.21 +/- 0.07, and a concentration of 46.11 +/- 0.52 mg/mL. The DMN loaded with CBD-NS demonstrated favorable intradermal dissolution and mechanical properties. It effectively increased the delivery of CBD into the skin, extended the action's duration in vivo, and enhanced bioavailability. CBD-NS DMN exhibited superior therapeutic efficacy and safety in a rat model of knee synovitis, significantly inhibiting TNF-alpha and IL-1 beta compared with the methotrexate subcutaneous injection method. Conclusion: NS technology effectively enhances the solubility of the poorly soluble drug CBD, while DMN facilitates penetration, extends the duration of action in vivo, and improves bioavailability. Furthermore, CBD has shown promising therapeutic outcomes in treating knee synovitis. This innovative drug delivery system is expected to offer a more efficient solution for the administration of highly lipophilic drugs akin to CBD, thereby facilitating high-dose administration.

Hypertrophic scars (HS), mainly caused by burns, trauma, and surgery, are associated with erythema, bumps, itching, and pain. The oral administration of Asiaticoside (AS) is a prevalent treatment for HS in clinical settings; however, its effectiveness is constrained due to its low bioavailability, necessitating high dosages for therapeutic impact. To mitigate this issue, we developed a layered dissolving microneedle (DMN) incorporating AS–ginsenoside Rb1–L–carnosine (A–G–C) at the tip for HS treatment. The tip layer of the DMNs comprised sodium carboxymethyl cellulose (CMC), while the base layer consisted of low-viscosity CMC to enhance mechanical strength. We examined its puncture performance, in vitro dissolution ability, and therapeutic effect on a rabbit ear model of HS. Histological analysis was performed by Hematoxylin and Eosin (H&E), Masson staining and Sirius red staining. The results demonstrated that the DMNs exhibited excellent puncture performance and dissolution rates. A-G-C DMNs were found to be effective in reducing scar thickness by measuring scar thickness changes. Histological analysis revealed that the A–G–C DMNs significantly reduced inflammation and collagen fiber deposition in scar tissue. Importantly, the therapeutic effect achieved with A–G–C DMNs was comparable to that of triamcinolone acetonide injection. These findings highlight the potential of DMNs loaded with A–G–C as a promising treatment modality for HS, offering improved bioavailability and therapeutic outcomes.

Microneedles (MNs) technology has been studied in transdermal drug delivery for more than 20 years with hundreds of clinical trials conducted. However, there are currently no commercially available MNs in medicine due to challenges in materials safety, cost-effective fabrication, and large-scale manufacturing. Herein, an approach for rapid and green fabrication of hydrogel microneedles (HMNs) based on infrared irradiation process was proposed for the first time. The optimized formulation consisted of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP), which acted as cross-linked materials and pore-forming agents, respectively. The manufacturing method involved placing MNs patches under infrared irradiation at 70 °C for 2 min and annealing to obtain HMNs with excellent swelling behavior, mechanical strength, and biocompatibility. When model drugs azelaic acid (AZA) and matrine (MAT) were loaded into HMNs systems, the chemical stability of MAT was significantly improved. Ex vivo transdermal delivery experiments indicated that HMNs could achieve synchronous release of AZA and MAT, and the 24-hour percutaneous permeability rates of both drugs were 73.09 ± 0.48 % and 71.56 ± 1.23 %, respectively. In-vivo pharmacokinetic studies, HMNs administration presented dose-dependent stable blood drug concentrations for both drugs. Additionally, prominent anti-tumor efficacy and biosecurity were observed in the drug-loaded HMNs group in the pharmacodynamic evaluation. In summary, the efficient, convenient, and low-cost fabrication method based on infrared irradiation offers the possibility of mass production of drug-loaded HMNs, showing potential for industrial manufacturing development.

Excessive melanin deposition in the skin leads to various skin pigmentation diseases, such as chloasma and age spots. The deposition is induced by several factors, including tyrosinase activities and ultraviolet-induced oxidative stress. Herein, we propose a multi-component, multi-pathway drug combination, with glabridin, 3-O-ethyl-L-ascorbic acid, and tranexamic acid employed as, respectively, a tyrosinase inhibitor, an antioxidant, and a melanin transmission inhibitor. Considering the poor skin permeability associated with topical application, dissolving microneedles (MNs) prepared with hyaluronic acid/poly(vinyl alcohol)/poly(vinylpyrrolidone) were developed to load the drug combination. The drug-loaded microneedles (DMNs) presented outstanding skin insertion, dissolution, and drug delivery properties. In vitro experiments confirmed that DMNs loaded with active ingredients had significant antioxidant and inhibitory effects on tyrosinase activity. Furthermore, the production of melanin both in melanoma cells (B16-F10) and in zebrafish was directly reduced after using DMNs. Clinical studies demonstrated the DMNs' safety and showed that they have the ability to effectively reduce chloasma and age spots. This study indicated that a complex DMN based on a multifunctional combination is a valuable depigmentation product worthy of clinical application.

To achieve the painless administration of interferon alpha 1b (rhIFNα-1b), a double-layered soluble polymer microneedle (MN) patch loaded with rhIFNα-1b was used to deliver rhIFNα-1b transdermally. The solution containing rhIFNα-1b was concentrated in the MN tips under negative pressure. The MNs punctured the skin and delivered rhIFNα-1b to the epidermis and dermis. The MN tips implanted in the skin dissolved within 30 min and gradually released rhIFNα-1b. The rhIFNα-1b had a significant inhibitory effect on the abnormal proliferation of fibroblasts and excessive deposition of collagen fibers in the scar tissue. The color and thickness of the scar tissue treated using the MN patches loaded with rhIFNα-1b were effectively reduced. The relative expressions of type I collagen (Collagen I), type III collagen (Collagen III), transforming growth factor beta 1 (TGF-β1), and α-smooth muscle actin (α-SMA) were significantly downregulated in scar tissues. In summary, the MN patch loaded with rhIFNα-1b provided an effective method for the transdermal delivery of rhIFNα-1b.

To reduce mucosal damage in the gastrointestinal tract caused by aspirin, aspirin microcrystals were loaded in soluble polymeric microneedle (MN) tips. Aspirin was prepared into aspirin microcrystals by jet milling. Aspirin microcrystals with particle sizes of 0.5–5 μm were loaded on MN tips with a height of 250 µm or 300 µm. The aspirin microcrystals suspended in a polymer solution were concentrated in the MN tips under negative pressure. The aspirin microcrystals had high stability in the MNs since they were not dissolved in solution during the fabrication process. The MN patch packaged in an aluminum-plastic bag containing silica gel desiccant can be stored at 4 °C. The MN tips implanted in the skin of Institute of Cancer Research (ICR) mice dissolved within 30 min. Isolated porcine ear skin was punctured by MNs with heights of 300 μm and 250 μm to depths of 130 μm and 90 μm, respectively. The fluorescent red (FR) release from MNs reached 98.59

To reduce mucosal damage in the gastrointestinal tract caused by aspirin,we developed a dissolvable polymeric microneedle(MN)patch loaded with aspirin.Biodegradable polymers provide mechanical strength to the MNs.The MN tips punctured the cuticle of the skin and dissolved when in contact with the subcutaneous tissue.The aspirin in the MN patch is delivered continuously through an array of micropores created by the punctures,providing a stable plasma concentration of aspirin.The factors affecting the stability of aspirin during MNs fabrication were comprehensively analyzed,and the hydrolysis rate of aspirin in the MNs was less than 2%.Compared to oral administration,MN administration not only had a smoother plasma concentration curve but also resulted in a lower effective dose of antiplatelet aggregation.Aspirin-loaded MNs were mildly irritating to the skin,causing only slight erythema on the skin and recovery within 24 h.In summary,aspirin-loaded MNs provide a new method to reduce gastrointestinal adverse effects in patients requiring aspirin regularly.

Background: Gestodene (GEST) is widely used in female contraception. It is currently being used as an oral contraceptive. However, unfortunately, oral contraceptives are often associated with several bothersome side effects and poor compliance. Therefore, a sustained delivery system for GEST to overcome these shortcomings is highly desirable. Objectives: The present study successfully developed a kind of novel dissolving microneedles (DMNs) with a potential for sustained release and a minimally invasive intradermal treatment of GEST. Methods: The dissolving microneedles containing GEST were fabricated using polyvinylpyrrolidone as the base material. The characteristics in vitro and pharmacokinetics in vivo of GEST-loaded DMNs were investigated. Results: The results showed that the microneedle could pierce the porcine skin and release the drug at an average dose of 20µg/cm2 daily for seven days. The pharmacokinetic experiment of the microneedles indicated that the plasma level of GEST in rats increased with increasing drug dosage, and the plasma drug concentration-time curves were much flatter compared with subcutaneous injection and oral administration. In addition, no cutaneous irritation was observed. Conclusions: GEST-loaded DMNs may be a promising intradermal sustained delivery system for contraceptive use.

Poor transdermal permeability limits the possibility of most drug delivery through the skin. Auxiliary permeable microneedles (AP-MNs) with a three-dimensional network structure can effectively break the skin stratum corneum barrier and assist in the transdermal delivery of active ingredients. Herein, we propose a simple method for preparing AP-MNs using polyvinyl alcohol and Eudragit NM30D for the first time. To optimize the formulation of microneedles, the characteristics of swelling properties, skin insertion, solution viscosity, and needle integrity were systematically examined. Additionally, the morphology, mechanical strength, formation mechanism, skin permeability, swelling performance, biocompatibility, and in vitro transdermal drug delivery of AP-MNs were evaluated. The results indicated that the microneedles exhibited excellent mechanical-strength and hydrogel-forming properties after swelling. Further, it proved that a continuous and unblockable network channel was created based on physical entanglement and encapsulation of two materials. The 24 h cumulative permeation of acidic and alkaline model drugs, azelaic acid and matrine, were 51.73 ± 2.61% and 54.02 ± 2.85%, respectively, significantly enhancing the transdermal permeability of the two drugs. In summary, the novel auxiliary permeable microneedles prepared through a simple blending route of two materials was a promising and valuable way to improve drug permeation efficiency.

As low-temperature storage and transportation of peptides require high costs, improving the dosage form of peptides can reduce costs. We developed a thermostable and fast-releasing stratified dissolving microneedle (SDMN) system for delivering exenatide (EXT) to patients with type 2 diabetes. Among the tested polymers, dextran and polyvinyl alcohol (PVA) were the best at stabilizing EXT under high-temperature storage for 9 weeks. The two polymers possess a relatively high glass transition temperature (Tg) and weak hydrogen bonding between PVA and EXT. Additionally, zinc sulfate (ZnSO4) had a stabilizing effect on EXT among the selected stabilizers, suggesting that EXT formed a dimer after coordination with zinc ions (Zn2+). In addition, the denaturation temperature (Tm) of EXT was increased by adding ZnSO4, thus stabilizing EXT. Accordingly, SDMNs consisting of a tip layer (dextran encapsulating the Zn2+-EXT complex) and a base layer (PVA) were fabricated. Within 2 min of implantation, the EXT loaded on the patch was quickly released into the skin. Transdermal pharmacokinetics studies showed that manufactured SDMNs generated comparable efficacy to subcutaneous injection. Significantly, the remaining EXT amount was not significantly different under storage at 40 degrees C and-20 degrees C for 3 months, supporting that the SDMN system had excellent delivery efficiency and stability, thus reducing the dependence on the cold chain.