Self-emulsifying drug delivery systems (SEDDS) are widely utilized to enhance oral drug absorption; however, limited epithelial permeability remains a major barrier, particularly for hydrophilic drugs and macromolecules. Medium-chain fatty acids are promising permeation enhancers (PEs) due to their transient effects on epithelial barriers. In this study, caprylic acid (C8) and capric acid (C10) were systematically evaluated as PEs in SEDDS, with emphasis on the influence of ionization state and mode of presentation within the formulation. SEDDS were modified by incorporating C8 or C10 either as free acids (SEDDS-C8/C10@Acid), as dispersed sodium salts (SEDDS-C8/C10@Salt), or by external addition of sodium salts after emulsification (SEDDS-C8/C10@extSalt). SEDDS-C8/C10@Acid significantly enhanced cellular internalization in Caco-2, HEK, and HeLa cells, achieving up to a 2.5-fold increase compared with unmodified SEDDS. In contrast, salt-based systems showed approximately 1.5-fold lower cellular association than acid formulations, while exhibiting improved cellular tolerability. Permeation studies revealed pronounced epithelial permeation across Caco-2 monolayers for salt-modified SEDDS, with lucifer yellow permeation increasing up to 7-fold for both C8 and C10 systems. Consistently, mucus interaction studies demonstrated enhanced diffusion for salt-based formulations. Differences between C8- and C10-containing systems were minor, indicating that alkyl chain length was less influential than ionization state and formulation format. Overall, incorporation of the free acid PE primarily enhanced cellular association via increased membrane partitioning, whereas incorporation of the corresponding sodium salt more effectively promoted mucus diffusion and epithelial permeation. These findings identify ionization state and formulation-dependent presentation as key design parameters for permeation-enhancing lipid-based drug delivery systems.
The unfolded protein response (UPR) has been mechanistically implicated in multiple ocular disorders, including age-related macular degeneration (AMD). Therapeutic intervention using an αB-crystallin-derived 'mini-cry' chaperone peptide has potential to restore proteostasis; however, its low molecular weight results in rapid ocular clearance. To prolong mini-cry's ocular effects, our team linked it with elastin-like polypeptides (ELPs). ELPs are thermoresponsive polymers that phase-separate into microscale coacervates. Provided ELPs do not interfere with biological activity, cry-ELPs could prolong intraocular retention and improve therapeutic effect. This study compares two cry-ELPs (cry-SI and cry-V96) designed to phase-separate following intravitreal administration. First, chaperone activity was assessed using tau protein aggregation assays, demonstrating that cry-V96 exhibited superior inhibition of tau seeding and fibril disaggregation. Second, modulation of the UPR was assessed in human retinal pigment epithelium cells using tunicamycin-induced stress. Both constructs suppressed PERK/ATF-4/CHOP signaling, with cry-V96 showing the most robust attenuation of ER stress. Third, cellular uptake and subcellular localization were analyzed by biochemical fractionation and Western blotting, revealing enhanced cellular uptake and association and stress-dependent nuclear localization of cry-ELPs, compared to controls. Fourth, the lead construct, cry-V96, was evaluated in vivo in rabbit eyes, where it formed a sustained intravitreal depot, exhibited prolonged retention, and showed no evidence of ocular toxicity by fluorescence imaging and optical coherence tomography (OCT). Finally, proteomic profiling using liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 59 proteins selectively enriched by cry-V96, implicating pathways involved in proteostasis, intracellular trafficking, and stress adaptation. Collectively, these findings establish cry-ELPs as multifunctional molecules that combine potent chaperone activity with sustained ocular delivery, providing a promising strategy for targeting UPR dysregulation in AMD and related degenerative diseases.
Hypothyroidism is conventionally treated with thyroid hormone replacement via synthetic hormones, namely levothyroxine (LT4), and in possible combination with liothyronine (LT3), both administered orally. The supratherapeutic peaks and subtherapeutic troughs of LT3 concentration after oral delivery may limit efficacy, as this pharmacokinetic profile does not mimic the relatively constant T3 levels found in normal physiology. Microneedle patches (MNPs) provide a simple-to-use delivery method that can be formulated to achieve controlled drug release for extended periods of time. Here, we developed a MNP for LT3 delivery into the skin as a first assessment of this approach. After examining a number of MNP formulations, we developed MNPs containing a range of different LT3 doses in a poly(vinylpyrrolidone)-based formulation. The MNs effectively punctured the skin and achieved average LT3 delivery efficiencies of 41–71
Microneedles have emerged as a promising technology for enhancing transdermal delivery. The micron-sized needles penetrate the stratum corneum with minimal pain and discomfort. Among the different microneedle types, hydrogel microneedles offer distinct advantages, including sustained drug release and biocompatibility. The present study aimed to optimize the formulation of hydrogel microneedles composed of Gantrez®S-97, a hydrophilic polymer, crosslinked with the sodium salt of hyaluronic acid at 80 °C to form a hydrogel matrix. Polyvinyl pyrrolidone, a synthetic water-soluble polymer, was incorporated to improve microneedles stability and enhance sustained drug release. Metoclopramide hydrochloride is a dopamine receptor antagonist with variable oral bioavailability and established clinical use in the management of chemotherapy-induced nausea, vomiting, and gastroesophageal reflux disorders. Metoclopramide-loaded hydrogel microneedle formulations were prepared with varying polymer compositions and evaluated by in vitro permeation studies. The optimized formulation demonstrated mechanical strength, uniform needle morphology, and a sustained drug release profile over 24 h. The hydrogel microneedles achieved up to an 18-fold enhancement in transdermal drug permeation compared to a conventional transdermal film.
Furylacryloyl-modified hyaluronan (F-HA) has emerged as an appropriate material for the fabrication of UV-crosslinkable, water-stable nanofibrous scaffolds with preserved porosity. However, the safety profile and in vivo applicability of F-HA have not yet been established. In this study, we present biological assessment of F-HA, including biodegradation studies and its first in vivo evaluation in C57BL/6J mice following both intravenous and intraperitoneal administration. The results demonstrate good tolerability under the tested conditions and confirm biodegradability. Additionally, we confirm the ability of composite nanofibers consisting of F-HA with established nanofiber-forming polymers, to incorporate active pharmaceutical ingredients (API), while retaining their porous structure and favorable mechanical properties. Importantly, the incorporation of F-HA alters the release profile of embedded API. Using octenidine dihydrochloride (OCT) as a model compound, we demonstrate sustained release from F-HA/lauroyl hyaluronan (L-HA) nanofibrous scaffolds in biologically relevant protein-containing media, while retaining its structural integrity, thus supporting its suitability for biomedical applications. These findings highlight the potential of F-HA as a versatile platform for the development of advanced nanofibrous biomaterials with translational relevance in topical wound healing and drug delivery.
Psoriasis, a chronic immune-mediated skin disease, lacks satisfactory treatment options due to the inherent limitations of conventional drug delivery: oral therapies often induce systemic toxicity, while topical agents fail to penetrate the thickened skin barrier. Anemoside B4 (AB4), a unique triterpenoidal saponin from Pulsatilla chinensis (content up to 9.7
Since the first review on imaging of intranasal drug delivery (INDD) was published in 2020, interest in the topic has increased, necessitating an update, which is the basis of the current review. INDD is a promising alternative for treating central nervous system (CNS) diseases. In vivo imaging is also important for therapy assessment, both clinically and preclinically. This review details studies that further our understanding of INDD and the fate of these therapies in the CNS using in vivo imaging. We performed a literature search using the keywords “Intranasal delivery” and “Imaging” from 2020 to 2025 and summarized these findings in the current updated review. This review is not comprehensive but provides examples of recent publications that explore the various treatments under development for nose-to-brain (N2B) therapeutic delivery through imaging. Imaging will include magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), gamma scintigraphy, and computed tomography (CT) for both humans and animals. Additional specialty topics pursued experimentally in animals include in vivo optical imaging techniques, including bioluminescence and fluorescence imaging. Finally, we discuss image-guided therapeutic techniques such as focused ultrasound and conclude with future directions. In this review, we introduce each imaging modality, describe its utilization, and outline its strengths and weaknesses, specifically in the context of N2B therapeutics.
Intracranial atherosclerosis (ICAS) is a leading cause of ischemic stroke. This study explored the mechanism of endothelial progenitor cells-derived exosomes (EPCs-exos) in ICAS. Rat EPCs were isolated, EPCs-exos were extracted and identified. A rat model of ICAS was established, and EPCs and EPCs-exos or lentiviral si-NCOA4 were injected into rats to observe the histopathological changes in cerebral microvessels, ferroptosis, angiogenesis, inflammatory indexes, and the NCOA4/FTH1 pathway. Hematoxylin and eosin staining was performed to observe the histopathology of cerebral microvascular tissue. EPCs were successfully isolated from rats and EPCs-exos were identified. EPC treatment inhibited the NCOA4/FTH1 pathway, hindered inflammatory responses and ferroptosis in ICAS rats, promoted neovascularization, and improved histopathology. EPCs-exos similarly reduced inflammatory responses and ferroptosis and promoted neovascularization in ICAS rats. In conclusion, EPCs‑exos reduce ferroptosis, attenuate inflammatory responses, and enhance cerebral neovascularization in ICAS rats in association with the NCOA4/FTH1 pathway modulation.
Pulmonary fibrosis (PF) represents the final stage of lung injuries, triggered mainly by viral infections. Pentoxifylline (PTX) is a hemorheologic drug that has been recently repurposed for the prophylaxis of PF. Nevertheless, it exhibits low oral bioavailability. This study aims to develop inhalable PTX-loaded novasomes with enhanced pulmonary deposition and improved therapeutic efficiency. PTX-novasomal nanovesicles were prepared using ethanol injection technique and characterized for particle size, zeta potential, and entrapment efficiency, adopting a central composite statistical design for optimization. The optimized PTX-novasomes were subsequently evaluated for in-vitro drug release and aerodynamic size characterization using Andersen Cascade Impactor. Furthermore, the optimized PTX-novasomes were characterized using transmission electron microscopy, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. Finally, an in-vivo pharmacodynamic study was performed in a bleomycin-induced PF rat model to assess the effects of inhaled PTX-novasomes on the inflammatory and fibrotic biomarkers, and fibrosis scoring via Masson’s trichrome stain. Results showed that the optimized Novasomes were successfully prepared as spheroidal nanosized vesicles (239.80 nm) with high PTX encapsulation (59.22
A dissolvable microneedle system (SFP-MNs) loaded with seven principal Sanfu Herbal Patch components was developed to assess transdermal delivery feasibility and therapeutic efficacy in a rat model of allergic asthma. SFP-MNs were fabricated using a two-step centrifugation-assisted template molding method and characterized in terms of morphology, mechanical strength, skin penetration capability, and in vitro drug release behavior. An ovalbumin (OVA)-induced allergic asthma model was established in Sprague–Dawley (SD) rats to investigate the in vivo performance of the microneedles. Pulmonary interstitial fluid was continuously sampled by microdialysis following transdermal administration, and drug concentrations were quantified using UPLC-MS/MS. Pharmacodynamic responses were evaluated by measuring histamine (HIS), immunoglobulin E (IgE), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) levels using ELISA, together with histopathological examination by hematoxylin and eosin (HE) and periodic acid–Schiff (PAS) staining. A pharmacokinetic-pharmacodynamic (PK-PD) model was subsequently established to characterize the relationship between drug exposure and therapeutic response. The prepared SFP-MNs exhibited excellent mechanical properties, efficient skin penetration, and sustained drug release. In vivo, SFP-MNs achieved effective transdermal delivery of the encapsulated components and produced superior therapeutic outcomes compared with an equivalent-dose conventional Sanfu Herbal Patch gel. Specifically, high-dose SFP-MNs markedly alleviated airway inflammation, reduced inflammatory biomarker levels, and attenuated pulmonary histopathological injury in allergic asthmatic rats. These findings demonstrate that SFP-MNs represent a promising transdermal drug delivery platform with the potential to replace conventional Sanfu Herbal Patch for the treatment of allergic asthma while providing sustained drug release and improved therapeutic efficacy.
Schizophrenia remains one of the most disabling mental disorders, and effective therapy is still limited by the difficulty of delivering drugs across the blood–brain barrier. Aripiprazole (Ari), a first-line atypical antipsychotic, exhibits restricted clinical performance due to poor solubility, extensive hepatic metabolism, and limited brain exposure. Herein, a novel intranasal nanocarrier system was developed to enable direct and sustained delivery of Ari to the brain. Chitosan nanoparticles (Cs-NPs) surface-modified with sodium dodecyl sulfate (SDS) were prepared by the ionic gelation method and optimized using a Box–Behnken design to evaluate the effects of SDS concentration, pH, and chitosan-to-tripolyphosphate ratio on particle size, zeta potential, and drug entrapment. The optimized formulation showed a mean particle size of 200 nm, a positive surface charge, and an entrapment efficiency of 76.98 ± 7.6
The liver is a pivotal organ for metabolic and immune homeostasis, playing an essential role in maintaining physiological balance. Globally, the increasing incidence and mortality of liver diseases constitute a critical public health issue. However, conventional therapies are often limited by their inability to precisely target the pathological microenvironment of the liver, frequently resulting in either insufficient efficacy or excessive tissue damage. With notable biocompatibility, a tunable porous architecture, and smart responsive capabilities, hydrogels hold considerable promise as drug carriers for treating liver diseases. This review evaluates the core design principles and therapeutic value of stimuli-responsive hydrogels in liver disease, compares hydrogel systems, details their responsive modes, and highlights recent progress in antitumor, antioxidant, anti-fibrotic, and immunomodulatory therapy. Ultimately, the present review examines the key challenges and future directions for translating stimuli-responsive hydrogels into more precise, safe, and personalized therapies for liver diseases.
Corneal drug permeability is a key determinant of topical ocular drug delivery efficiency, yet its quantitative prediction remains challenging due to experimental noise and limited generalizability across drugs. Herein, we systematically integrated ex vivo drug and formulation corneal permeability data and developed a hybrid machine learning framework that jointly incorporates intrinsic and formulation-level information to quantitatively characterize corneal drug permeation under high-noise and drug cold-start conditions. We curated the first comprehensive ex vivo corneal apparent permeability coefficient (Papp) dataset containing 575 formulation records covering 65 active pharmaceutical ingredients (APIs), 85 penetration enhancers, and 4 animal species. We also curated a molecular dataset of 205 drugs representing intrinsic permeation potential, which was used as prior information for formulation-level prediction. Systematic comparison across multiple machine learning algorithms showed that Tabular Prior-data Fitted Network (TabPFN) achieved the best performance, with R² values of 0.54 for molecular permeability and 0.88 for formulation-level prediction. However, performance degraded in scenarios involving unseen drugs. Incorporating molecular permeability as a prior feature reduced cold-start error by 14.6
The blood brain barrier (BBB) limits effective treatment for cerebellar diseases. Region-specific parameterization and safety data for MRI-guided focused ultrasound (MRgFUS) BBB opening (BBBO) in the cerebellum are scarce. The goal of this study is to establish safety and feasibility of cerebellar BBBO for antibody delivery. Mice received i.v. AF680 IgG and microbubbles immediately prior to sonication at 0.30 or 0.45 MPa peak negative pressure (1.15 MHz, 10 ms bursts, 2 s burst period, 60 bursts). BBBO was quantified by contrast-enhanced T1-weighted MRI (9.4T) and assessed for recovery at 12 h. Radiologic safety was evaluated by T2-weighted MRI. Acoustic emissions were analyzed via real-time passive cavitation detection, and acoustic simulations estimated the derated pressure caused by skull incidence angle. IgG delivery was quantified by ex vivo IVIS epifluorescence imaging and immunofluorescence analysis. Safety assessments included cardio-respiratory monitoring, body weight, motor function, and neuropathology assessment of endpoint H E. Both regimens yielded cerebellar BBBO without radiologic evidence of injury. BBB integrity was restored by 12 h. While the higher pressure increased MRI and cavitation signals, IgG delivery was similarly enhanced (> 2-fold vs. sham) by FUS, irrespective of peak negative pressure. Heart rate, respiratory rate, body weight, and motor function were unchanged by FUS, and neuropathologic evaluation revealed no hemorrhage, inflammation, vacuolation, or architectural abnormalities. FUS enables safe, transient BBBO in the cerebellum and significantly enhances antibody delivery without measurable physiologic, functional, radiologic, or histologic injury. These findings establish a foundation for expansion of pharmacologic and theranostic delivery strategies directed to the cerebellum.
Lung cancer remains a leading cause of cancer-related mortality worldwide, while the clinical utility of irinotecan-derived therapies is often constrained by poor drug solubility, suboptimal biodistribution, and systemic toxicity. To overcome these limitations, we developed polymeric nanomicelles co-loading 7-Ethyl-10-hydroxycamptothecin (SN38), the active metabolite of irinotecan, and quercetin, a naturally occurring flavonoid with intrinsic antitumor activity, for nebulized inhalation delivery. The dual-drug nanomicelles (SN38/QU-PPM) were prepared by nanoprecipitation and exhibited a uniform particle size distribution, excellent stability, and pH-responsive drug release under acidic conditions. In vitro studies demonstrated that quercetin co-loading enhanced cellular uptake of the nanomicelles and promoted intracellular accumulation of SN38, resulting in significantly greater cytotoxicity against LLC-Luc lung cancer cells compared with SN38-loaded nanomicelles alone. In an orthotopic lung cancer model, nebulized inhalation of SN38/QU-PPM achieved a 3.33-fold higher pulmonary SN38 concentration than intravenous administration at 24 h. Nebulized SN38/QU-PPM also exhibited superior antitumor efficacy, achieving a tumor inhibition rate of 80.7
Peptide drugs have gained considerable attention as new molecular entities, due to their high target specificity. However, oral delivery of peptides remains a major challenge, and current formulation approaches typically achieve only low single-digit bioavailability, prompting exploration of synergistic strategies to improve absorption. In this work, a self-unfolding foil device, designed for unidirectional drug release in close proximity to the intestinal mucosa, is combined with a potent permeation enhancer-based ionogel formulation for exploitation of synergies from two different oral delivery approaches. The choline decanoate ionogel is loaded into the foil, and insulin release optimized through hydrophilic surface modification and tailored cavity design. In vivo evaluation in rats demonstrate a bioavailability of 12.5
Fungal keratitis (FK) is a severe ocular disease that may cause blindness in severe cases. The only FDA-approved first-line treatment drug is natamycin (NAT). However, NAT bioavailability is less than 2
Sublingual films are promising drug delivery platforms due to their rapid hydration and drug release, and the incorporation of nanoparticles can further improve drug solubility, bioavailability, and therapeutic efficacy. Therefore, this study aims to identify, map, and synthesize the available evidence on nanocomposite films for sublingual drug delivery. This scoping review was conducted in accordance with the Joanna Briggs Institute (JBI) framework and reported following the PRISMA extension for Scoping Reviews (PRISMA-ScR). A total of 226 articles were initially identified, of which 31 met the inclusion criteria (2014–2025). Among them, microemulsions, and cyclodextrin complexes were the most frequently investigated systems (6/31), followed by nanofibers (5/31), polymeric nanoparticles (4/31), niosomes (3/31), and nanocrystals (3/31). Overall, these technologies were primarily selected to enhance drug solubility, dissolution, and mucosal transport. Other nanostructures, including nanocapsules, liposomes, micelles, and transferosomes, were each reported (1/31). Regarding film-forming matrices, synthetic and semisynthetic polymers were predominantly used (26/31), particularly HPMC, PVA, and PVP, whereas natural polymers were underexplored (5/31), highlighting a reliance on conventional pharmaceutical excipients. However, few studies provided robust pharmacological evidence (2/31) or comprehensive toxicity assessments (5/31), revealing important gaps. Moreover, 13 studies performed permeation evaluations, indicating that a substantial proportion of the evidence remains limited to physicochemical characterization without functional assessment of drug transport across the mucosa. Similarly, bioavailability was investigated in fewer than one-third of the studies (9/31), although the available evidence generally demonstrated improved bioavailability compared with conventional formulations. Furthermore, significant methodological heterogeneity in disintegration protocols and mucosal models hinders the comparability of clinical outcomes. Overall, this scoping review highlights nano-based sublingual films as promising strategies to improve drug bioavailability, while emphasizing the need for more standardized methodologies and rigorous pharmacological and safety evaluations to facilitate their translational advancement toward clinical application.
Diabetic wounds often lead to significant therapeutic challenges due to impaired vascularization, chronic inflammation, and poor drug penetration. This study presents a polyallylamine hydrochloride-fucoidan (PAH.Fc) hydrogel-based microneedle patch for site specific delivery of IGF1-incorporated exosomal vesicles obtained from adipose-derived stem cells (ADSC-Exos) to diabetic wounds. The average size of IGF1-loaded ADSC-Exos was measured as 261.81 nm. The fabricated microneedles exhibited swelling ratios between 228.0
Adeno-associated virus (AAV)-based gene therapy has demonstrated transformative potential in treating hereditary hearing loss (HHL). Investigating factors that influence AAV transduction in target and non-target organs is critical for improving therapeutic precision and safety. Given the postnatal maturation of the murine inner ear and compartmentalized structure of the cochlea, we evaluated whether developmental age or delivery routes affect AAV-PHP.eB tropism in cochlear hair cells (HCs) and adjacent brain regions. Following round window membrane (RWM), posterior semicircular canal (PSCC), or utricle delivery, neonatal mice showed robust OHC transduction (vs. minimal in juveniles), while IHC transduction remained consistently high across age groups. Across all three delivery routes, brain AAV transduction was significantly higher in neonates than in juveniles. Despite this, AAV genome copies were more highly enriched in the injected inner ear than in the brain at both ages. Dye-tracing experiments demonstrated distinct spatial distribution patterns following three inner ear delivery routes, with the cochlear aqueduct (CA) identified as the primary conduit for intracranial spread post-injection. These findings provide guidance for the design of studies in mouse models of deafness, particularly with respect to cochlear hair cell subtype targeting, therapeutic timing, and safety assessment of AAV-PHP.eB-based therapies for hearing loss.
