Psoriasis is a chronic autoimmune skin disorder primarily driven by dendritic cells (DCs). However, the full therapeutic potential of antipsoriatic agents like calcipotriol (Cal) hinges on the precise and efficient delivery to DCs. Herein, a nanovehicle fabricated using keratinocyte-derived apoptotic vesicles (apoEVs) is proposed to enhance drug accumulation in DCs and synergistically modulate DC function. Specifically, the phosphatidylserine exposed on the apoEV surface serves as an "eat-me" signal, facilitating specific recognition and engulfment by DCs. This process mimics the natural efferocytic clearance of apoptotic keratinocytes by DCs in the skin. Moreover, apoEVs intrinsically inhibit DC maturation by eliciting efferocytosis-mediated immunosuppressive signals. To enable transdermal administration, Cal-loaded apoEVs were integrated into dissolvable microneedles (MNs). As a consequence, the Cal-apoEV MNs demonstrated superior capability in reprogramming DCs from a pro-inflammatory to a tolerogenic phenotype, thereby suppressing the pathogenic inflammatory loop and ameliorating psoriatic symptoms. Notably, Cal-apoEV MNs remodeled the psoriatic immune microenvironment toward a tolerogenic state, characterized by enhanced regulatory T cell infiltration. The present study reveals that the keratinocyte-derived nanovehicles can not only enhance the accumulation of Cal in DCs but also synergistically reprogram DCs, providing a promising strategy for treating immune-mediated skin diseases.

Smart responsive microneedles for drug delivery and therapeutic applications.

Microneedle technologies in emerging strategies for non-transdermal drug delivery.

Effect of transdermal testosterone on postmenopausal sexual desire: placebo-controlled randomized clinical trial.

Development of AI-assisted 3D-printed degradable hydrogel microneedles for transdermal delivery of progesterone-loaded solid lipid nanoparticles: a novel approach to slowing Alzheimer's disease progression.

Osteoporosis treatment using alendronate (ALN) is limited by poor oral bioavailability and gastrointestinal side effects. To address this limitation, this study developed a graphene oxide (GO)-enhanced soluble microneedle (MN) system for transdermal administration of ALN to treat osteoporosis. The MNs were fabricated from polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) using a two-step casting method, forming a drug-loaded core-barrier outer layer. The incorporation of GO significantly improved mechanical strength, with penetration efficiency reaching 66∼88%, and enhanced swelling capacity (PP/GO-ALN swelling ratio: 299%). In vitro release studies showed no significant difference between PP-ALN and PP/GO-ALN MNs in a dialysis bag model, while ex vivo skin permeation demonstrated that PP/GO-ALN MNs achieved significantly higher cumulative drug permeation (1069.53µg/cm2) over 24 h compared to PP-ALN MNs (712.89µg/cm2). Furthermore, GO conferred notable antibacterial activity, and the PP/GO-ALN formulation synergistically promoted osteoblast proliferation (cell viability: 107.42%, p < 0.05). These findings demonstrate that the GO-ALN MN system possesses mechanical properties, transdermal delivery, antibacterial effects, and biocompatibility. It provides a highly promising non-invasive strategy for the treatment of osteoporosis.

ROS-responsive tegafur-pheophorbide a conjugate-loaded microneedles for deep drug delivery and chemo-photodynamic therapy of superficial tumors

Although mRNA vaccines have revolutionized modern vaccinology, significant challenges persist owing to their dependence on ultra-cold storage, patient discomfort, and logistical complications associated with intramuscular (IM) injections. Dissolving microneedles (DMNs) are a promising alternative by enabling minimally invasive transdermal administration that directly engages skin-resident immune cells, while their fabrication compromises fragile mRNA. Moreover, previous studies have emphasized antibody-mediated immunity rather than exploiting their capacity for strong T cell responses. In this study, we developed an mRNA-liposome vaccine via DMN (ML-DMN) to preserve the mRNA activity in DMN formulations and boost immune cell activation. Incorporating excipients into the formulation retained the mRNA integrity during fabrication, as demonstrated by in vitro luciferase assays. In vivo administration of ovalbumin (OVA) mRNA via ML-DMN promoted rapid migration and activation of antigen-presenting cells (APCs) in draining lymph nodes (dLNs) within 24h, initiating an innate immune response. This led to robust OVA-specific T cell activation, proliferation, and secretion of key cytokines, confirming a potent adaptive immune response with lower mRNA doses than IM injections. These results suggest that ML-DMN systems have significant potential to overcome current mRNA vaccine limitations by improving mRNA integration and immune cell targeting, offering a viable strategy for future vaccine development.

Cold chain dependence and inconvenient needle/syringe-based injections limit the global deployment of adenoviral (Ad) vectored vaccines, which play significant roles in veterinary vaccinology and offer an effective tool to protect humans against potential pandemics/endemics. Herein, a new Ad5-FMD vaccine stabilizing and delivery technology is presented, termed as Stabilized Prophylactic Adenovirus Nanostructure Delivery via Microneedles (SPAND-MN), which enables room-temperature storage and easy-to-use, painless transdermal administration of Ad vectored vaccines. It is demonstrated the success of SPAND-MN platform to deliver replication-defective Adenovirus serotype 5 (Ad5) vaccine vectors expressing various antigens, including Green Fluorescent Protein (GFP), Luciferase (Luc), and Foot-and-Mouth Disease (FMD) capsid proteins. The SPAND-MN formulation preserved transduction capacity of the Ad5 vaccines after exposure to an accelerated temperature (at 60°C) and a long-term storage at 45°C for 1 month. In vitro and in vivo studies confirmed effective transduction efficiency, dose delivery, and biocompatibility of the SPAND-MN platform. In vivo safety assessments revealed no cytotoxicity, systemic inflammation, and organ toxicity. SPAND-MNs maintained immunogenicity equivalent to injections of the stock refrigerated vaccines even after thermal challenges. These results demonstrate the potential of SPAND-MNs to offer a powerful, easy-to-use, cold-chain free, and painless transdermal skin patch for Ad5 vaccination.

Losartan potassium (LP) is an angiotensin II receptor blocker (ARB) with established clinical utility in the management of hypertension and diabetic nephropathy. Oral delivery of LP is hampered by extensive hepatic first-pass metabolism and highly variable bioavailability (25–35%), making it a compelling candidate for transdermal administration. The stratum corneum, however, presents a formidable physicochemical barrier that restricts passive permeation of most drug molecules. The present study describes the development and comprehensive physicochemical characterization of LP-loaded ethosomes elastic, ethanol-enriched phospholipid vesicles—incorporated into a hydroxypropyl methylcellulose (HPMC K100M)-based matrix transdermal patch. Six ethosomal formulations (EP-1 to EP-6) were prepared by the cold-membrane extrusion method by systematically varying phosphatidylcholine (300–400 mg), cholesterol (75–100 mg), and ethanol content (20–40% v/v). The optimized formulation (EP-6) displayed a mean particle size of 176.3 ± 3.9 nm, a polydispersity index of 0.241 ± 0.01, a zeta potential of −34.8 ± 1.2 mV, and an encapsulation efficiency of 85.7 ± 1.5%. Ethosomal vesicles were incorporated into a solvent-cast HPMC matrix patch demonstrating acceptable physicochemical attributes including tensile strength (4.8 ± 0.3 N/mm²), moisture content (3.2 ± 0.4%), and drug content uniformity (97.8 ± 0.9%). In vitro membrane permeation studies performed using Strat-M® synthetic membrane a well-validated, animal-free surrogate for human skin—demonstrated a steady-state flux of 62.4 ± 2.3 µg/cm²/h for the EP-6 patch, representing a 4.3-fold enhancement over a conventional matrix patch. Release kinetics conformed to an anomalous (non-Fickian) diffusion model. Confocal laser scanning microscopy using fluorescently labeled ethosomes confirmed deep penetration through the Strat-M® membrane layers, validating the mechanistic basis of the observed permeation advantage. Stability evaluation under ICH Q1A(R2)-prescribed conditions demonstrated that the patch retained physicochemical integrity over six months. These results collectively support the viability of an LP ethosomal transdermal patch as a controlled, animal-free-validated delivery platform for antihypertensive therapy.

Metal-organic frameworks for topical and transdermal therapeutics.

Application of drugs through the transdermal route is preferable over other routes of drug delivery because of the ease of drug administration and reduced systemic side effects. Mirtazapine is a BCS class II noradrenergic and specific serotonergic drug and shows poor solubility and bioavailability. This study aims to develop and optimize a mirtazapine-loaded lipid-based transethosomal gel to enhance transdermal drug delivery and bypass first-pass metabolism. The current study is an attempt to minimize the systemic side effects associated with oral administration of mirtazapine and to avoid first pass metabolism by administering the drug through the skin. Transethosomes were formulated using the cold method and optimized via Box-Behnken design by varying phospholipid, surfactant, and ethanol concentrations. The optimized formulation (F-16) exhibited high entrapment efficiency (75.92%) and cumulative drug permeation (73.62%) after 6 hours. Multiple characterization tests confirmed nano-sized, stable vesicles with a zeta potential of -34.1 mV and particle size of 479.3 nm. The transethosomal dispersion was incorporated into a Carbopol gel and evaluated for pH, viscosity, spreadability, drug content, and skin permeation. Ex-vivo studies showed enhanced skin permeation from the gel compared to the dispersion. Stability tests confirmed physical integrity over 60 days, while skin irritation and toxicological studies in animal models indicated excellent biocompatibility, with no signs of inflammation or organ toxicity. These findings and the study suggests that the transethosomal gel formulation is a promising and safe approach for transdermal delivery of mirtazapine, potentially improving its bioavailability and therapeutic effectiveness resulting in bypassing first pass metabolism.

The present study was conducted in the pediatric urology outpatient clinic of a tertiary referral hospital and included children with persistent symptoms of overactive bladder (OAB) despite prior conservative management. To compare the efficacy and safety of oral and transdermal oxybutynin in the treatment of non-neurogenic OAB in children. The present prospective, randomized controlled clinical study was conducted at a tertiary pediatric urology outpatient clinic between January 1 and July 1, 2019. A total of 90 children were initially enrolled. After exclusion of seven patients due to incomplete follow-up data, 83 patients were included in the final analysis. Patients were randomized in a 1:1 allocation ratio to receive either oral oxybutynin (n = 42) or transdermal oxybutynin (n = 41). Symptom severity and treatment response were assessed using the Dysfunctional Voiding and Incontinence Symptom Score (DVISS), bladder diary, and uroflowmetric parameters. Pre- and post-treatment values were compared within and between groups. Adverse effects were documented based on patient-reported symptoms and clinical observation. Continuous variables in two dependent groups were compared using the Wilcoxon test. Continuous variables in two independent groups were analyzed using the Mann-Whitney test. Fisher's exact test was used to compare proportions between groups. Both groups demonstrated statistically significant improvements in DVISS, voided volume, and urinary frequency after treatment ( P < 0.05). No significant difference in treatment efficacy was found between oral and transdermal administration. Adverse reactions were observed in 40.5% (n = 17) of group 1 and 43.9% (n = 18) of group 2 ( P = 0.826). However, non-skin-related systemic adverse events were significantly more frequent in the oral oxybutynin group compared with the transdermal group (38% vs. 9.8%, P = 0.004). None of the adverse effects observed in either group were severe enough to require discontinuation of treatment. Transdermal oxybutynin is as effective as oral oxybutynin in managing pediatric non-neurogenic OAB, with a more favorable systemic side effect profile. It represents a viable alternative for patients who experience difficulty with oral medication or intolerance to systemic anticholinergic side effects.

Topical and transdermal drug and cosmetic development is advancing across industry; however, the efforts may in part be hindered by paucity of data on the fate of chemicals in human skin, which depend on protein-mediated transport and biotransformation of such chemicals. A label-free mass spectrometry-based proteomics approach was used to comprehensively quantify drug metabolizing enzymes and transporters in the fractionated epidermis and dermis of 17 healthy Caucasian human skin samples. Over 1000 proteins were identified for cytosolic and membrane components, and abundance were obtained using a modified HiN (high 3/2 ion intensity) approach (without using standards). Key findings included high interindividual variability in the expression of phase I and II enzymes (eg, aldehyde dehydrogenase 2, carboxylesterase 1, glutathione S-transferase P1, and glutathione peroxidase 3) and solute carrier transporters (eg, SLC25A5, SLC25A6). Notably, several metabolic enzymes, previously uncharacterized in human skin, were quantified in the membrane fractions, including glutathione S-transferases (GSTs) such as GSTM3 (12.2 pmol/mg protein) and GSTP1 (5.55 pmol/mg protein). Subcellular localization analysis revealed that many quantified proteins were associated with mitochondrial or membrane compartments, reinforcing the functional diversity and compartmentalized nature of dermal metabolism. Furthermore, strong correlations in enzyme and transporter expression were observed between the dermis and epidermis (Spearman's ρ > 0.85). This dataset provides the most detailed quantification to date of drug metabolizing enzymes and transporters in human skin and offers critical input parameters for dermal physiologically based pharmacokinetic modeling applications. These quantitative insights improve the accuracy and clinical relevancy of in vitro in vivo extrapolations related to dermal drug metabolism and disposition for chemicals applied to the skin or those that come into contact with the skin inadvertently. Integration of this proteomic dataset into physiologically based pharmacokinetic frameworks will enhance the scientific reliability, applicability across product applications and regulatory acceptance of skin-based models for drug development and safety evaluation. SIGNIFICANCE STATEMENT: Understanding drug metabolism and transport in human skin is essential for predicting dermal absorption and safety. This study provides the most comprehensive proteomic dataset of metabolizing enzymes and transporters in epidermis and dermis, revealing high interindividual variability, previously unquantified enzymes, and strong layer correlations, supporting improved dermal physiologically based pharmacokinetic model development.

Biologics, or Biological therapeutics, are among the most intriguing therapeutic agents with the potential to transform the treatment of chronic diseases completely. However, the primary challenge with biologics is their need for parenteral administration, which leads to poor patient compliance and treatment failure. Delivering biologics via a non-invasive oral route could help achieve high patient compliance, but this is hindered by gastric barriers. Carrier-based systems, mucoadhesive systems, transdermal administration, implantable pumps, peptide modification techniques such as cyclization, PEGylation, glycosylation, etc., and co-formulation with permeation enhancers have been tried for the above-mentioned purpose, but with only minimal success. Therefore, in this short review, we gave an overview of the novel and emerging drug delivery technology - Ingestible Injectable or Ingestible Microneedle Robotic devices, which facilitate enhanced oral biologics uptake with higher compliance.

Mastitis is a common disease in dairy cows, mainly caused by Staphylococcus aureus and Escherichia coli. Berberine (BBR) has antibacterial and anti-inflammatory potential, but its application is limited due to poor oral absorption and difficulty in reaching mammary tissue. To address this, this study developed a BBR-loaded composite ethosome hydrogel (BBR-CEH) to achieve targeted mammary delivery through local transdermal administration. The experimental results showed that BBR-CEH has good chemical stability and biosafety. Subsequently, a mouse mastitis model was established by intraductal injection of 50 µL of bacterial mixture (E. coli:S. aureus = 1:1, each at 1 × 107 CFU/mL). The results showed that after BBR-CEH treatment, the mRNA expression of TNF-α (tumor necrosis factor-alpha), IL-6 (interleukin-6), and IL-1β (interleukin-1 beta) was significantly decreased, the mRNA expression of ZO-1 (zonula occludens-1), Occludin, and Claudin-4 was significantly increased, and Bax/Bcl-2 (Bcl-2-associated X protein/B-cell lymphoma 2) was significantly reduced (p < 0.01), indicating alleviation of mastitis by reducing inflammation, improving tight junctions, and inhibiting apoptosis. Finally, network pharmacology and in vivo experiments confirmed that its mechanism involves the NF-κB (nuclear factor kappa-B) and PI3K/Akt (phosphoinositide 3-kinase/protein kinase B) pathways. Thus, topical BBR-CEH may represent a promising new strategy for mastitis treatment.

Abstract Veterinary drug delivery must balance efficacy, ease of administration, and animal welfare. Traditional methods, such as oral and injectable routes, pose challenges due to species-specific variations, stress during administration, and the need for repeated dosing. Emerging transdermal systems, particularly microneedle patches, offer a minimally invasive alternative that enhances drug absorption while reducing handling stress toward animals and improving compliance. Microneedle technology enables controlled and sustained drug release, making it particularly effective for pain management, vaccine delivery, and hormone therapies. By facilitating the transdermal administration of analgesics, microneedles deliver long-lasting pain relief with fewer interventions, improving the treatment of acute and chronic conditions in veterinary medicine. The use of biodegradable materials further enhances safety, eliminates the need for patch removal, and minimizes environmental impact. However, challenges such as species-specific skin permeability, formulation stability, and regulatory approval must be addressed for widespread adoption. This review examines the evolution of veterinary drug delivery, emphasizing microneedle-based technologies and their potential to improve pain management and therapeutic outcomes. By overcoming existing limitations, these systems could transform treatment approaches, simplify administration, and enhance overall animal care. Continued research and development will be essential for optimizing these technologies and expanding their applications in both clinical and agricultural settings. Graphical abstract

The anti-parasitic drug moxidectin is a frontline treatment for sarcoptic mange in bare-nosed wombats (Vombatus ursinus), a disease causing significant animal welfare issues and instances of local population declines. Despite widespread usage, knowledge of species-specific pharmacokinetics of moxidectin in bare-nosed wombats is still limited. This study describes the clinical pharmacokinetics of moxidectin by intravenous, subcutaneous, and transdermal routes of administration in bare-nosed wombats. Plasma moxidectin concentration was assessed by liquid chromatography mass spectrometry and analysed by Bayesian hierarchical modelling. Plasma clearance was 1.11-1.85 mL/min/kg. The subcutaneous route showed biphasic absorption, dominated by a slow terminal absorption phase (80% of the effective dose of moxidectin was absorbed in this phase) with a half-life of approximately 631 h (26.3 days). The transdermal route had an estimated half-life of 21.78 h (1308) min. The average bioavailability was 0.59% and 95.7% by the transdermal and subcutaneous route, respectively. This detailed insight into the pharmacokinetics of moxidectin in bare-nosed wombats provides a crucial foundation for the design of treatment regimens, whilst also highlighting the inefficiency of transdermal delivery.

Cubosomes (QBS) are self-assembled, nanostructured lipid carriers characterized by a bicontinuous cubic liquid crystalline architecture with a three-dimensional honeycomb-like morphology. Their unique internal structure allows simultaneous encapsulation of hydrophilic, lipophilic, and amphiphilic compounds, enabling sustained, site-specific, and targeted drug delivery through various routes, including oral, ocular, nasal, transdermal, and vaginal administration. Composed primarily of amphiphilic lipids such as Glyceryl Monooleate (GMO) and stabilized with surfactants like Pluronic F-127, QBS exhibits superior biocompatibility, structural integrity, and long-term colloidal stability. QBS are typically fabricated using either top-down or bottom-up strategies. Top-down approaches such as high-pressure homogenization, probe sonication, and spray drying fragment bulk cubic phases into nanosized dispersions, ensuring scalability and uniformity. Conversely, bottom-up methods, including the hydrotrope technique, vortex dispersion, and solvent evaporation, enable spontaneous QBS formation under mild conditions ideal for thermolabile actives. Physicochemical properties depend on lipid-to-stabilizer ratios, solvent composition, and processing parameters. Characterization techniques such as Dynamic Light Scattering (DLS), Small-Angle X-ray Scattering (SAXS), Transmission Electron Microscopy (TEM), and Confocal Laser Scanning Microscopy (CLSM) confirm particle size, morphology, and internal nanostructure. Zeta potential and MTT assays evaluate stability and cytocompatibility, while in vitro and ex vivo studies assess drug entrapment, release, and permeation behaviour. QBS represent an advanced class of lyotropic liquid-crystalline nanocarriers with high drug-loading potential, excellent biocompatibility, and controlled-release performance. Their multifunctional versatility underscores their promise as next-generation platforms for targeted and sustained drug delivery applications.

Abstract: Nanoemulsions have emerged as versatile nanoscale delivery systems capable of enhancing drug permeation, stability, and therapeutic efficiency across transdermal, dermal, and oral routes. In diabetes management, conventional therapies often suffer from limited bioavailability, rapid systemic clearance, and the need for frequent dosing, resulting in fluctuating glycemic control and reduced patient adherence. Nanoemulsion-based formulations offer a promising alternative by improving solubility, enhancing mucosal and skin penetration, protecting labile drugs, and enabling controlled or targeted release. Recent advances in semisolid and hybrid nanoemulsion systems have further strengthened their potential by addressing long-standing challenges related to physical stability, dose conversion, and scalability. Nanotechnology-driven approaches, including PEGylation, ligand functionalization, and encapsulation within lipid or polymeric nanocarriers, have shown particular promise for peptide-based antidiabetic drugs such as GLP-1 analogues. These modifications enhance gastrointestinal stability, prolong circulation time, and improve targeted delivery to metabolic tissues. Additionally, nanoemulsions support multimodal delivery, enabling both transdermal insulin options and oral delivery strategies that bypass first-pass metabolism. Beyond pharmaceuticals, nanoemulsion technology is widely used in skincare, agriculture, food processing, and the cosmetic industries—illustrating its flexibility in formulation, safety, and cost-effective manufacturing. For diabetes, however, challenges remain, including physicochemical instability, potential toxicity of surfactants, regulatory hurdles, and the need for standardized scale-up methods. This review provides a comprehensive overview of emerging nanoemulsion platforms for diabetes therapy, highlighting recent innovations, therapeutic advantages, and key translational challenges. By integrating advancements in formulation science and nanotechnology, nanoemulsions represent a rapidly evolving framework with significant potential to transform future diabetes management.