Drug Delivery And Translational Research[JOURNAL]
Sun
200 papers
Deferoxamine-coated mesoporous silica nanoparticles sustainably reduce iron overload in HepG2 cells. A protein corona study on plasma from hemochromatotic mice.
Gisbert-Garzarán M, de-la-Torre P, Pablos JL … +7 more , García-Consuegra I, Díaz-Díaz S, Liria-González I, Salinas AJ, Flores AI, Sánchez-Salcedo S, Morán-Jiménez MJ
Drug Deliv Transl Res · 2026 Jul · PMID 42399537 · Publisher ↗
Elevated iron levels, as seen in hemochromatosis, can damage vital organs. Although chelators are effective at removing excess iron, they have poor pharmacokinetics, which requires repeated doses and leads to adverse sid...
Elevated iron levels, as seen in hemochromatosis, can damage vital organs. Although chelators are effective at removing excess iron, they have poor pharmacokinetics, which requires repeated doses and leads to adverse side effects. Here, we report on the synthesis of mesoporous silica nanoparticles (MSN) functionalized with the clinically used chelator deferoxamine (DFO). The nanoparticles have been physicochemically characterized, demonstrating the successful grafting of the chelator and chelating features comparable to those of the free drug. The MSN-DFO have been tested in a hepatocellular carcinoma cell line (HepG2), producing an expected decline in cell viability due to intracellular iron chelation, which affects metabolic processes. Nonetheless, it has been shown that cell function is restored when the nanochelator is cleared from the cells, highlighting its overall biocompatibility. Interestingly, MSN-DFO exhibited a more gradual and prolonged iron removal process in iron-overloaded HepG2 cells than DFO did. Finally, in preparation for an in vivo administration, the protein corona formed on the MSN-DFO has been thoroughly analyzed, revealing clear differences depending on the plasma origin (wild type vs. hemochromatotic mice), highlighting the role that the protein corona fingerprint might have as a predictor of diseases, and shedding light on how this nanochelator would behave in vivo.
Optimizing snake fang-inspired microneedles for transdermal liquid drug delivery.
Liu Y, An M, Yang Y … +2 more , Bai J, Zhou R
Drug Deliv Transl Res · 2026 Jul · PMID 42397612 · Publisher ↗
Transdermal microneedles (MNs) offer a minimally invasive and highly compliant approach for delivering macromolecular therapeutics. However, the clinical translation of conventional conical and pyramidal MNs is hindered...
Transdermal microneedles (MNs) offer a minimally invasive and highly compliant approach for delivering macromolecular therapeutics. However, the clinical translation of conventional conical and pyramidal MNs is hindered by an intrinsic mechanical trade-off: minimizing tip diameter reduces insertion force but increases fracture susceptibility, whereas enlarging the base improves structural robustness at the cost of higher skin insertion resistance. Furthermore, closely spaced MN arrays frequently suffer from the "bed-of-nails" effect, which precludes adequate tissue penetration. Inspired by the open-groove fangs of opisthoglyphous snakes, which evolved for low-resistance tissue puncture, we designed and systematically optimized snake fang-inspired microneedles (SF-MNs). Using a three-layer hyperelastic Neo-Hookean skin model, we conducted finite element analyses on 27 distinct SF-MN configurations to evaluate their static strength and dynamic insertion mechanics. The optimal SF-MN structure (500 [Formula: see text] length, 30 [Formula: see text] groove depth, 10 [Formula: see text] tip diameter) demonstrated superior lateral structural stability (safety factor > 0.6) and achieved significantly lower insertion forces compared to size-matched conical MNs. Notably, SF-MN arrays mitigated the "bed-of-nails" effect, narrowing the critical inter-needle spacing triggering range to 396-402 [Formula: see text]-markedly lower than the 440-700 [Formula: see text] range of conventional arrays. By leveraging groove-induced tissue diversion and contact area reduction, these biomimetic arrays enable deeper skin penetration, offering a robust and highly efficient platform for transdermal drug delivery in chronic disease management.
Radiopaque microsphere-hydrogel composite for extended-release intratumoral immunotherapy in a large animal model.
Patel AK, Mohammad IS, Kortylewski M … +8 more , Rosen ST, Kessler J, Ressler J, Chao CH, Choi TJ, Lall C, Guerra C, Boas FE
Drug Deliv Transl Res · 2026 Jul · PMID 42390735 · Publisher ↗
Intratumoral injection of immune stimulants could potentially reverse the immunosuppressive tumor microenvironment, but the injected drug rapidly washes out into the systemic circulation. This results in systemic toxicit...
Intratumoral injection of immune stimulants could potentially reverse the immunosuppressive tumor microenvironment, but the injected drug rapidly washes out into the systemic circulation. This results in systemic toxicity, and reduced efficacy, potentially requiring daily injections to generate an antitumor immune response. To address this problem, we developed an extended-release hydrogel that retains the immunotherapy agent at the injection site, and releases it over several days, even in highly vascular liver tumors. The extended-release hydrogel is a composite material containing drug-loaded microspheres (for sustained, tunable drug release), embedded in a radiopaque cross-linked hydrogel (for local retention). Using these new intratumoral drug carriers, we demonstrate the ability to safely deliver a wide range of different immunotherapy agents (cytokines, oligonucleotides, small molecules) into pig liver tumors, with no acute systemic toxicity. The microsphere gel reduces burst release by 7.8x (compared to microspheres), and increases half-life by > 15x (compared to hydrogel). Thus, the immunotherapy-loaded microsphere gel enables sustained intratumoral delivery of immune stimulants from a single injection, with low systemic toxicity.
Redispersible nanoalum-adjuvanted hepatitis B vaccine microneedles with enhanced immunogenicity.
Kim M, Kim H, Byun S … +7 more , Kwon MJ, Baek SK, Kim C, Kim TH, Lee JM, Kwak K, Park JH
Drug Deliv Transl Res · 2026 Jun · PMID 42365188 · Publisher ↗
Nanoalum has been widely investigated as an advanced aluminum-based adjuvant; however, its performance in solid vaccine formulations remains poorly understood because administration depends on reconstitution after storag...
Nanoalum has been widely investigated as an advanced aluminum-based adjuvant; however, its performance in solid vaccine formulations remains poorly understood because administration depends on reconstitution after storage and delivery. Here, a hepatitis B surface antigen (HBsAg) vaccine was formulated with nanoalum, freeze-dried, and delivered using a powder-attached microneedle array patch (P-MAP). Formulations were screened based on redispersion in PBS after lyophilization to identify a lead composition (HBsAg: Alhydrogel: PAA: Trehalose = 1:5:5:50, w/w/w/w; F12), and the effects of preparation pH (7.4 vs. 5.6) were evaluated. The optimized formulation maintained a nanoscale dispersed state after PBS reconstitution (< 250 nm), whereas PEG-substituted and PAA-free formulations showed severe aggregation (> 2 μm). When administered as liquid intradermal injections, preparation pH produced minimal differences in immune responses. In contrast, clear divergence emerged following freeze-drying and P-MAP delivery. The pH 5.6 formulation (G9) generated the highest IFN-γ ELISpot response among all P-MAP groups while maintaining strong HBsAg-specific IgG responses and an increased IgG2a/IgG1 tendency. The PAA-free formulation (G10), which exhibited poor redispersion after reconstitution, produced reduced and more variable antibody responses. Notably, formulations displaying nanoscale redispersion consistently outperformed aggregated formulations in both humoral and cellular immune responses. These findings demonstrate that post-lyophilization redispersion is a critical quality attribute for nanoalum-containing solid vaccine formulations and that formulation conditions governing redispersion can substantially influence immune outcomes following P-MAP delivery.
Mannose receptor-targeted MSC-derived exosomes as a high-affinity delivery platform for liver sinusoidal endothelial cells.
Lee JW, Lee JS, Choi K … +5 more , Lee MR, Han SK, Baik SK, Park YS, Kim MY
Drug Deliv Transl Res · 2026 Jun · PMID 42360611 · Publisher ↗
Liver sinusoidal endothelial cells (LSECs) play a crucial role in the progression of liver fibrosis. While mesenchymal stem cell-derived exosomes (MSC-Exos) hold potential for liver regeneration, their therapeutic effica...
Liver sinusoidal endothelial cells (LSECs) play a crucial role in the progression of liver fibrosis. While mesenchymal stem cell-derived exosomes (MSC-Exos) hold potential for liver regeneration, their therapeutic efficacy is often limited by poor target specificity and rapid clearance. Here, we developed mannose receptor-targeting MSC-Exos (Man-Exos) by incorporating DSPE-PEG-Mannose via a post-insertion method to enhance LSEC-specific delivery. The physicochemical stability and targeting efficiency of Man-Exos were evaluated both in vitro and in vivo. Man-Exos exhibited high stability in various conditions and showed significantly enhanced binding affinity to LSECs compared to non-targeted exosomes. Notably, in a co-culture system of LSECs and macrophages, Man-Exos demonstrated superior selectivity for LSECs. In vivo biodistribution studies further confirmed that Man-Exos predominantly accumulated in the liver, specifically colocalizing with LSECs for up to 48 h. Our findings suggest that Man-Exos can serve as a highly efficient and stable delivery platform for LSEC-targeted therapy, providing a promising strategy for enhancing the translational potential of exosome-based regenerative medicine in liver fibrosis.
Oral nanoparticle-encapsulated enzyme replacement therapy for mucopolysaccharidosis type I (MPS-I): a proof of concept study.
Álvarez JV, Lis-Lopez L, Rodrigues D … +11 more , Pena C, Bravo SB, Díaz-Tomé V, Rodríguez SC, López-Valverde L, Rodiño-Janeiro BK, Colón C, Luzardo-Álvarez A, de Castro MJ, Otero-Espinar FJ, Couce ML
Drug Deliv Transl Res · 2026 Jun · PMID 42323476 · Publisher ↗
Mucopolysaccharidosis type I (MPS-I) is a rare, multisystemic lysosomal storage disease (LSD) caused by mutations in the IDUA gene, which encodes the enzyme alpha-L-iduronidase. Current treatments include hematopoietic s...
Mucopolysaccharidosis type I (MPS-I) is a rare, multisystemic lysosomal storage disease (LSD) caused by mutations in the IDUA gene, which encodes the enzyme alpha-L-iduronidase. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy (ERT), administered via weekly intravenous infusions. ERT is of limited efficacy owing to its inability to reach critical tissues such as the brain and bone. To address these limitations, this study explores a novel method to improve drug delivery to target organs and simplify administration: oral administration of enzyme encapsulated within nanostructured lipid carriers (NLC). Encapsulation of ERT within NLC enabled effective oral administration. In vitro analysis showed that our NLC formulation was as effective as intravenous ERT in correcting enzyme activity and reducing glycosaminoglycan (GAG) accumulation in fibroblasts from MPS-I patients, when administered periodically. Permeability studies confirmed passage across the intestinal barrier. Proteomic analyses demonstrated normalization of protein expression in energetic pathways related to hexose metabolism, and significant improvements in protein dysregulation in the cytoskeleton, cellular trafficking, lysosomal function, GAG biosynthesis and degradation, and the extracellular matrix. Furthermore, in vivo studies in MPS-I knockout (KO) mice demonstrated biodistribution of NLC-encapsulated enzymes to all tissues affected by the disease, including passage across the blood-brain barrier and access to poorly vascularized bone. These findings suggest that oral administration of ERT via NLC encapsulation represents a significant advancement in MPS-I treatment, enabling drug delivery to previously inaccessible areas. This study opens important avenues of research for future therapeutic strategies targeting LSDs.
Scalable diclofenac lauryl ester prodrug nanoparticles: a promising strategy for reducing inflammation associated with intervertebral disc degeneration.
Hussain S, Arif A, Bano P … +5 more , Saleem R, Rajput SN, Zhang L, Khan I, Mujeeb-Ur-Rehman
Drug Deliv Transl Res · 2026 Jun · PMID 42315786 · Publisher ↗
As the most frequent clinical problem, intervertebral disc degeneration (IVDD) and associated inflammatory pain are still a big challenge, thus there is a need for improved and more lasting therapeutic approaches. In thi...
As the most frequent clinical problem, intervertebral disc degeneration (IVDD) and associated inflammatory pain are still a big challenge, thus there is a need for improved and more lasting therapeutic approaches. In this study, a lipidic prodrug of diclofenac, Diclofenac Lauryl Ester (L-DCF), was synthesized and formulated into nanoparticles (Nanofenac-L) using the ethanol injection method followed by microfluidization. The encapsulation efficiency of Nanofenac-L was > 97% with sustained drug release, releasing around 65% of the diclofenac in 48 h. The therapeutic potential of Nanofenac-L was evaluated in rat intervertebral disc-derived nucleus pulposus cells. Nanofenac-L was found to be more effective than free Diclofenac Sodium (DCF-Na) in terms of anti-inflammatory activity, which was confirmed with significant suppression of COX-2 and Substance P. Furthermore, Nanofenac-L increased the expression of antioxidant genes in cells, such as SOD1, GPX1 and PRDX1. Preventive treatment was found to have shown therapeutic value whereas the curative treatment yielded a significant therapeutic effect indicating the possibility of Nanofenac-L to alleviate inflammation as well as to slow down disease progression. Altogether, these results suggest that Nanofenac-L could represent a promising long-lasting anti-inflammatory, pain relieving and antioxidant nanotherapeutic. Comprehensive preclinical and clinical evaluation is essential to translate these findings into viable therapies.
Understanding DMG: current treatment options and prospective solutions using nanoparticles.
Mohamed A, Lyzlov A, Prasad R … +6 more , Moats RA, Krieger MD, Desai VR, Margol AS, Chiarelli PA, Upreti M
Drug Deliv Transl Res · 2026 Jun · PMID 42307690 · Publisher ↗
Diffuse Midline Gliomas (DMGs), which include the subset formerly known as Diffuse Intrinsic Pontine Glioma (DIPG), are associated with an extremely poor prognosis and a five-year survival rate below 2-3%. The devastatin...
Diffuse Midline Gliomas (DMGs), which include the subset formerly known as Diffuse Intrinsic Pontine Glioma (DIPG), are associated with an extremely poor prognosis and a five-year survival rate below 2-3%. The devastating prognosis stems from an inherently invasive nature, a deep, anatomically restricted location, rapid cellular drug efflux mediated by transporters such as P-glycoprotein (ABCB1) and breast cancer resistance protein (BCRP/ABCG2), and an immunologically "cold" microenvironment. Coupled with limited Blood-Brain Barrier (BBB) permeability, these biological factors render conventional, therapeutic strategies minimally effective. Nanoparticles (NPs) offer novel opportunities to enhance drug delivery across the BBB by improving penetration-primarily through strategies such as receptor-mediated transcytosis or localized delivery approaches-thereby concentrating therapy at the tumor site, lowering systemic toxicity, and enabling integration of diagnostic imaging. Crucially, the distinct and targetable biology of this H3K27-altered disease, including alterations in ACVR1, PDGFRA, and CDK4/6 pathways, makes it a key focus for current nanomedicine research.This review evaluates how NP strategies have potential to provide adaptive solutions to overcome the hurdles in therapeutic development for DMG. It details the major NP platforms-including liposomal, polymeric, inorganic, and carbon-based nanomaterials- focusing on design principles like size, surface charge, and stealth coating to enhance targeted delivery for passive accumulation or receptor-mediated transport across the BBB. It explores theranostic applications that integrate real-time imaging (MRI, PET) with targeted, personalized therapy. Additionally, the role of high-Z metal NPs as radiosensitizers is discussed, highlighting their ability to increase DNA damage in tumor cells while protecting healthy tissue. Although early studies demonstrate strong in vitro efficacy, challenges in BBB penetration, intratumoral distribution and nanomaterial scaling still impede successful in vivo translation. Nanomedicine overcomes critical DMG barriers by enabling targeted, sustained, image-guided therapy. Achieving meaningful survival benefit for patients with DMG requires a multidisciplinary approach bridging neuro-oncology, advanced imaging, and nanomaterials development. Future research must prioritize four key areas: (1) optimizing NP properties for superior brainstem penetration, (2) leveraging DMG-specific markers for active delivery, (3) integrating theranostics for real-time monitoring, and (4) developing scalable, clinically compliant manufacturing.
Electrospun fibers as cosmetic carriers: A systematic review of formulation components and clinical evidence.
Tipduangta P, Than YM, Worajittiphon P … +3 more , Titapiwatanakun V, Dilokthornsakul P, Goh CF
Drug Deliv Transl Res · 2026 Jun · PMID 42295703 · Publisher ↗
Cosmetic electrospun fibers have emerged as an innovative skincare delivery platform, attracting growing research interest due to their structural tunability, functional versatility, and scalability for industrial produc...
Cosmetic electrospun fibers have emerged as an innovative skincare delivery platform, attracting growing research interest due to their structural tunability, functional versatility, and scalability for industrial production. Despite extensive research into formulation design for improved active delivery, the evidence linking formulation parameters to cosmetic efficacy remains fragmented and inconclusive. This systematic review critically assesses the influence of electrospun fiber formulations on active ingredient release, skin permeation, and clinical dermatological efficacy. A comprehensive literature search was conducted across PubMed, Embase, and Scopus databases from inception to June 2024 using predefined keywords, while study selection, screening and data extraction were performed using Covidence. The findings demonstrated that electrospinning configurations and formulation parameters, particularly polymer selection, polymer blending strategies, and the nature of incorporated active substances, play decisive roles in determining fiber morphology, dissolution, and release behaviors. Fibers composed of single hydrophilic polymers were well suited for rapid or immediate release applications, whereas hydrophobic-hydrophilic polymer blends enabled sustained delivery profiles such as those required for overnight facial masks. Across in vitro and ex vivo studies, electrospun fibers consistently enhanced the skin permeation of active compounds. Importantly, available clinical trials, although limited in number, provided emerging evidence of their practical efficacy, with reported improvements primarily in skin hydration and elasticity. Collectively, these findings underscore the promise of electrospun fibers as a reliable and effective cosmetic delivery platform that supports evidence-based skincare innovation while aligning with broader objectives of promoting skin health, product safety, and consumer well-being in accordance with Sustainable Development Goal 3.
Guanidinium-rich scyllo-inositol molecular transporter enables enhanced transdermal and intracellular delivery of vitagen.
Sepay N, Yoon S, Yu SH … +1 more , Im J
Drug Deliv Transl Res · 2026 Jun · PMID 42295702 · Publisher ↗
Transdermal drug delivery (TDD) is a non-invasive and painless drug delivery method, making it a compelling alternative to conventional methods, such as oral intake and intravenous injection. Although TDD holds promise,...
Transdermal drug delivery (TDD) is a non-invasive and painless drug delivery method, making it a compelling alternative to conventional methods, such as oral intake and intravenous injection. Although TDD holds promise, it faces challenges owing to the complex structure of the human skin. In particular, the stratum corneum (SC) serves as a significant barrier to drug absorption, hindering the passage of larger molecules. The TDD of vitagen, a stable L-ascorbic acid derivative with antioxidant properties, remains challenging because of its limited skin permeability. To address this issue, we prepared an ionic complex between vitagen and a synthesized guanidine-rich molecular transporter, scyllo-inositol-G6 (scyllo-G6), as a permeation enhancer (vitagen/scyllo-G6). This ionic complex showed improved skin permeability compared to vitagen alone with negligible cytotoxicity, indicating that the molecular transporter is biocompatible. Franz cell diffusion experiments demonstrated that scyllo-G6 exhibited a higher penetration coefficient with vitagen than other common penetration enhancers, such as oleic acid and menthol. Additionally, our findings revealed that the vitagen/scyllo-G6 complex had a notably greater inhibition effect on intracellular reactive oxygen species (ROS) than when vitagen was complexed to other permeation enhancers. Furthermore, FITC-labelled vitagen (FITC-vitagen) complexed with scyllo-G6 (FITC-vitagen/scyllo-G6) exhibited improved cellular uptake and penetrated deeper into tissue sections in a mouse model than FITC-vitagen conjugated to an arginine hexamer (Arg6), indicating that scyllo-G6 is a more effective skin penetration enhancer than Arg6. These findings suggest that utilizing scyllo-G6 as molecular transporter to enhance the skin permeability of vitagen is a promising strategy for TDD of vitagen.
Transdermal delivery and anti-inflammatory efficacy of Mitragyna speciosa extract transdermal patch for local inflammation management: in vitro, ex vivo, and in vivo investigations.
Tuntiyasawasdikul S, Junlatat J, Tabboon P … +2 more , Limpongsa E, Jaipakdee N
Drug Deliv Transl Res · 2026 Jun · PMID 42295701 · Publisher ↗
This study aimed to fabricate and characterize a polymeric matrix-type transdermal patch containing Mitragyna speciosa ethanolic extract (MSE) using an Eudragit RL100/polyvinylpyrrolidone (ERL/PVP) matrix. Eight differen...
This study aimed to fabricate and characterize a polymeric matrix-type transdermal patch containing Mitragyna speciosa ethanolic extract (MSE) using an Eudragit RL100/polyvinylpyrrolidone (ERL/PVP) matrix. Eight different MSE polymeric matrices with varying ERL/PVP ratios, solvent-type permeation enhancers, and MSE loadings were successfully prepared using the solvent casting technique. All polymeric matrices had average thickness of 272.5-316.0 μm with mitragynine content of 198.45-280.86 µg/cm². ATR-FTIR indicated a lack of intermolecular interactions between MSE and ERL or PVP. Mitragynine release followed a square root of time dependence, with a rate of 12.74-17.72 µg/cm/h, regulated by a diffusion-controlled process. Ex vivo skin absorption using porcine ear skin showed that mitragynine permeated with initial permeation flux of 1.55-2.84 µg/cm/h. Inclusion of 10% diethylene glycol monoethyl ether enhanced mitragynine skin deposition and permeation efficiency, yielding total skin absorption of 30.88% of the applied dose at 24 h. An anti-inflammatory study using carrageenan-induced paw edema in Wistar rats demonstrated the efficacy of MSE patch administration through systemic effects (dorsal region) and local effects (paw area). Expression of pro-inflammatory genes (IL-6, iNOS, and TNF-α) in the paw tissue treated with the MSE patch was significantly reduced compared to that with the placebo. In vivo skin absorption demonstrated that MSE patches delivered mitragynine systemically at a low concentration (< 0.48 µg/mL), while remaining safe and not inducing skin irritation. The information in this study highlights the potential of polymeric matrix as a simple, conventional, noninvasive alternative transdermal carrier for MSE to alleviate local inflammation and pain associated with inflammatory conditions.
Numerical modelling for hollow pyramidal microneedle-based drug-loaded particles delivery for controlled drug release.
Nadda R, Das DB
Drug Deliv Transl Res · 2026 Jun · PMID 42289613 · Publisher ↗
The present study develops a comprehensive computational framework to model the coupled transport, deposition, and release behaviour of Ibuprofen-loaded (IBU) core-shell sub-micron particles (MPs) delivered by dual-chann...
The present study develops a comprehensive computational framework to model the coupled transport, deposition, and release behaviour of Ibuprofen-loaded (IBU) core-shell sub-micron particles (MPs) delivered by dual-channel hollow microneedles (HMNs). The model integrates laminar fluid flow within the MN lumen and Darcy-based porous flow in the viable epidermis (VE) and dermis layers of the skin. In addition, the model incorporates advection-diffusion of the dissolved drug (IBU) after release from the core-shell particles, along with Lagrangian particle transport and core- and shell-controlled drug release kinetics. The setup allows simultaneous evaluation of particle transport, deposition, residence time, and spatial drug-release profiles. The effects of polymer chemistry, particle size (2 to 8 μm), dual-channel HMN lumen diameter (40 to 70 μm), and needle array configuration have been systematically investigated. Core and shell particles made of polyvinyl alcohol (PVA), polylactic acid (PLA), and polyglycolic acid (PGA) have been used in this study. It has been found that material and size dependent transport occurs, with PVA shells enabling rapid penetration and early release, whereas PGA shells promote sustained delivery. Smaller particles accumulate and release more drug due to greater penetration through the porous skin microstructure, whereas larger particles exhibit transport limitations. An increase in dual-channel lumen diameter from 40 μm to 70 μm resulted in greater penetration through the porous skin microstructure, whereas larger particles exhibited an 80% rise in particle deposition and a corresponding increase in cumulative IBU release from 18% to 32.4%. Increasing HMN array density enhances parallel transport channels, resulting in a significant increase in drug release from 8% for a single needle to 50.64% for a 4 × 4 array at 500 s, corresponding to a more than six-fold improvement. Overall, this study presents a mechanistic, particle-resolved modelling approach that enhances understanding of HMN-mediated TDD and informs rational system design.
Hyperbranched poly(β-amino ester)s-mediated delivery of engineered Klotho mRNA rescues senescence and restores cellular homeostasis in aged and Klotho deficient iMSCs.
Zaidi SAA, Yong H, Padhiar AA … +7 more , Faqeer A, Song J, He L, Zaidi SSA, Khan N, Zhou D, Zhou G
Drug Deliv Transl Res · 2026 Jun · PMID 42265429 · Publisher ↗
A decline in Klotho expression is a defining feature of aging and contributes to cellular dysfunctions. Here, we developed an engineered IVT Klotho mRNA incorporating ARCA capping. Ψ-modification and poly(A) tailing, del...
A decline in Klotho expression is a defining feature of aging and contributes to cellular dysfunctions. Here, we developed an engineered IVT Klotho mRNA incorporating ARCA capping. Ψ-modification and poly(A) tailing, delivered using a hyperbranched poly(β-amino ester) (HPAE)-based platform to enhance intracellular delivery and translation. Using CRISPR edited KL (-/-) iPSCs and derived iMSCs, we show that loss of KL induces a robust senescent phenotype characterized by activation of p53-p21-p16 pathways, mitochondrial depolarization, elevated ROS, and altered Ca homeostasis. A single dose of an engineered KL mRNA restored its protein expression within 24 h and rapidly suppressed senescence markers at both transcript and protein levels. Mechanistically, KL mRNA treatment rejuvenated mitochondrial functions by restoring membrane potential, increasing SOD2 expression, reducing mitochondrial ROS, and normalizing Ca homeostasis consistent with Klotho's known roles. Importantly, the rejuvenation response was selective; old and KL (-/-) iMSCs displayed substantial recovery. Whereas young iMSCs remained largely unaffected, indicating that KL acts as a stress responsive factor. These findings support engineered KL mRNA as a promising non-integrating transcript-based therapeutic approach for ameliorating senescence-associated cellular dysfunction. This work supports the potential of KL mRNA to restore regenerative capacity in older conditions and highlighting mRNA-based therapeutics as a promising direction for anti-aging and regenerative medicine.
In honor of Prof. Véronique Préat.
Beloqui A, Rieux AD, Malfanti A … +1 more , Alonso MJ
Drug Deliv Transl Res · 2026 Jul · PMID 42257823 · Publisher ↗
Abstract loading — click title to view on PubMed.
Avidity-by-design: spatial control of T7 peptide presentation on polymersomes dictates blood-brain barrier transport fate.
Lopes CDF, Basile M, Barbieri V … +3 more , Cosenza V, Pfeifer P, Battaglia G
Drug Deliv Transl Res · 2026 Jun · PMID 42251181 · Publisher ↗
Targeting the transferrin receptor (TfR) holds promise for drug delivery across the blood-brain barrier (BBB), but conventional strategies suffer from competition with endogenous ligands and suboptimal trafficking. To ov...
Targeting the transferrin receptor (TfR) holds promise for drug delivery across the blood-brain barrier (BBB), but conventional strategies suffer from competition with endogenous ligands and suboptimal trafficking. To overcome these limitations, we engineered a library of T7 peptide-functionalised pH-responsive polymersomes with precise control over ligand density and ligand insertion depth (δ) within a poly(ethylene glycol) (PEG) corona. We generated nanoparticles with δ values ranging from 0.3 (deeply inserted ligands) to 1.0 (fully exposed ligands), enabling systematic evaluation of how spatial ligand presentation influences BBB interactions. In vitro studies revealed that δ = 1.0 polymersomes exhibited efficient transcytosis, whereas δ = 0.6 polymersomes promoted endothelial retention, a divergence likely linked to differential receptor clustering and trafficking kinetics. Notably, TfR-mediated transport occurred independently of PACSIN2, distinguishing it from tubular transcytosis pathways observed with LRP1-targeted systems. These findings establish avidity-by-design as a strategy to tailor nanocarriers for either BBB penetration or vascular targeting, offering a modular platform for neurological therapeutics.
The electrical and chemical hypoxia-optimized (ECHO) bioreactor system enables scalable production of functionally preserved NK-exosomes validated in a syngeneic lung cancer model.
Nathani A, Padakanti SC, Dev S … +1 more , Singh M
Drug Deliv Transl Res · 2026 Jun · PMID 42251180 · Publisher ↗
Natural killer (NK) cell-derived exosomes represent promising cell-free immunotherapeutics, yet clinical translation is limited by low production yield and lack of scalable manufacturing strategies. Here, we developed a...
Natural killer (NK) cell-derived exosomes represent promising cell-free immunotherapeutics, yet clinical translation is limited by low production yield and lack of scalable manufacturing strategies. Here, we developed a modified vertical-wheel bioreactor incorporating controlled electrical and hypoxia-mimetic conditioning to enhance NK-exosome production while preserving biological functionality. The Electrical and Chemical Hypoxia-Optimized (ECHO) Bioreactor increased exosome yield by 10.1 ± 0.4 -fold compared to conventional culture (n = 3), without altering particle size, zeta potential, or canonical exosomal marker expression. In vitro, NK-Exo and NK-Exo-CE reduced LLC cell viability to 37.8 ± 3.1% and 18.6 ± 2.4%, respectively, at 1 × 10¹¹ particles/mL (p < 0.001). Combination therapy with paclitaxel further reduced viability to 9.4 ± 1.8% (p < 0.001). In a subcutaneous LLC tumor model, NK-Exo and NK-Exo-CE reduced tumor volumes to 912 ± 104 mm³ and 824 ± 96 mm³, respectively, compared to 1187 ± 132 mm³ in controls (p < 0.001), while NK-Exo-CE + PTX achieved 348 ± 57 mm³ (~ 3.4-fold reduction vs. control; p < 0.001) at the end of day 16. Immune profiling as determined by flow cytometry demonstrated increased CD8⁺ T cell infiltration (8.9 ± 1.1% to 35.7 ± 2.6%, p < 0.001) and reduced regulatory T cells (28.7 ± 1.8% to 10.4 ± 1.2%, p < 0.001) in combination-treated tumors. Western blot analysis confirmed elevated cleaved caspase-3, cleaved PARP, Granzyme B, FasL, Phospho-NF-κB-p65 and reduced Ki-67 and PDL1 in NK-Exo-CE + PTX tumors. Collectively, electro-hypoxic bioreactor conditioning enables scalable NK-exosome production without compromising physicochemical integrity or antitumor efficacy, addressing a key translational barrier in extracellular vesicle therapeutics.
Injectable pre-vascularized alginate-collagen hydrogel with sustained delivery of miR-133a-loaded lipid nanoparticles for myocardial repair.
Gil-Cabrerizo P, Simón-Yarza T, Imaz AM … +5 more , Lugli E, Paredes J, Aldazábal J, Garbayo E, Blanco-Prieto MJ
Drug Deliv Transl Res · 2026 Jun · PMID 42243568 · Publisher ↗
Myocardial infarction (MI) remains a leading cause of heart failure, and current therapies fail to prevent cardiomyocyte loss or support effective tissue regeneration. Injectable hydrogels (HGs) have emerged as promising...
Myocardial infarction (MI) remains a leading cause of heart failure, and current therapies fail to prevent cardiomyocyte loss or support effective tissue regeneration. Injectable hydrogels (HGs) have emerged as promising platforms for delivering therapeutic cues and structural support; however, few systems simultaneously integrate vascular guidance and RNA therapeutics. Here, we have developed a thermosensitive alginate-collagen HG pre-vascularized with endothelial cells and fibroblasts and engineered for the sustained release of cardioprotective miR-133a encapsulated in ionizable lipid nanoparticles (LNPs). MiR-133a-LNPs formulated by microfluidics display optimal physicochemical properties, efficient endosomal escape and preserved bioactivity. The HG exhibits shear-thinning, self-healing behavior and temperature-triggered gelation, enabling minimally invasive delivery and controlled miRNA release. Embedded cells remain viable, organized into early microvascular networks, and secrete pro-angiogenic factors. MiR-133a released from the HG attenuates oxidative stress-induced apoptosis in cardiomyoblasts. This multifunctional platform integrates structural support, pro-angiogenic signaling and sustained anti-apoptotic miRNA delivery, offering a promising strategy to mitigate early myocardial injury and promote key regenerative processes following MI.
Advancing transdermal drug delivery using translational data and mechanistic based modeling.
Rose JP, Shrestha N, Patil YP … +3 more , Tan JS, Bharadwaj R, Subramony JA
Drug Deliv Transl Res · 2026 Jun · PMID 42236660 · Publisher ↗
Transdermal drug delivery systems (TDDS) offer patient-centric advantages as drug dosage forms, but candidate selection for transdermal within early discovery remains challenging due to high attrition rates (> 40%) and l...
Transdermal drug delivery systems (TDDS) offer patient-centric advantages as drug dosage forms, but candidate selection for transdermal within early discovery remains challenging due to high attrition rates (> 40%) and limited predictive screening methodologies. This work introduces a mechanistic, data-driven in silico model to accelerate candidate selection for transdermal drug delivery, leveraging translational data from four approved products. The model simulates passive diffusive transport across the epidermis, focusing on two critical parameters: the partition coefficient between patch and skin (K) and the diffusion coefficient in the stratum corneum, which together determines the overall transdermal flux. Model reliability was validated using data from four marketed transdermal drugs-fentanyl, rivastigmine, nicotine, and lidocaine-with strong agreement to in vitro and in vivo results. In addition to predictive performance, the platform enables mechanistic interpretation of key transport parameters, establishing in vitro/in vivo correlations via scaling of partition coefficients, and providing a thermodynamic rationale for observed relationships with drug molecular properties. This approach supports rational design and early feasibility assessment of molecules for transdermal delivery systems, supporting efficient identification and optimization of candidate molecules for pre-clinical and clinical translation.
Solid microneedle booster as an enhanced microneedling platform for the treatment of androgenetic alopecia.
Shin J, Song J, Kim P … +2 more , Yang H, Jung H
Drug Deliv Transl Res · 2026 Jun · PMID 42228320 · Publisher ↗
Solid microneedle (SMN) is used to enhance transfollicular delivery in androgenetic alopecia (AGA); however, user-dependent kinematics can generate irregular microchannels that require sequential drug application. Here,...
Solid microneedle (SMN) is used to enhance transfollicular delivery in androgenetic alopecia (AGA); however, user-dependent kinematics can generate irregular microchannels that require sequential drug application. Here, we developed a one-step solid microneedle booster (SMB) that combines spring-driven perpendicular stamping with simultaneous liquid dosing. This circumvents the spatial and temporal mismatch inherent in traditional two-step methods, improving microchannel reproducibility and early transport. In porcine skin, rhodamine B mapping exhibited higher microchannel surface coverage for SMB than that of the roller at 20 matched applications, with SMB producing deeper penetration. Functional delivery was evaluated by Franz diffusion using ascorbic acid as a hydrophilic probe of microchannel-assisted permeation. Across the various tested conditions, SMB consistently produced a stronger early-phase permeation enhancement than that of the roller, and this early advantage was reflected in the cumulative delivery at later time points. SMB-assisted minoxidil (MXD) delivery accelerated hair regrowth in vivo compared with roller-assisted delivery under matched treatment settings, and histological analysis supported these outcomes as it revealed a greater enrichment of deep follicles in the SMB + MXD groups. Collectively, SMB provides a directionality-controlled, one-step microneedling platform that enhances the early, front-loaded transport and promotes follicular maturation, with AGA serving as a representative model for the broader applications of dermatologic delivery.
Enhancing skin moisture and anti-aging by DL-α-tocopherol loading sodium alginate-based hydrogel microneedles.
Awan KM, Yu H, Wang L … +8 more , Haroon M, Basit A, Hu J, Feng J, Malik MO, Ahmad D, Raza S, Majeed H
Drug Deliv Transl Res · 2026 Jun · PMID 42223799 · Publisher ↗
Effective skin moisturization is essential for combating age-related skin deterioration and maintaining overall skin health. This study investigates the development and characterization of DL-α-tocopherol-loaded sodium a...
Effective skin moisturization is essential for combating age-related skin deterioration and maintaining overall skin health. This study investigates the development and characterization of DL-α-tocopherol-loaded sodium alginate (SA)-based hydrogel microneedles (MNs) using a polyethylene glycol diglycidyl ether (PEGDE) crosslinking strategy for sustained, non-invasive antioxidant delivery and enhanced skin hydration. Three hydrogel formulations, SAP1, SAP2 and SAP3, were prepared with varying PEGDE to SA molar ratios, resulting in distinct swelling behaviors and crosslinking densities. SAP1 exhibited the highest swelling ratio, while SAP3 showed the lowest, which influenced the drug release profiles. SAP1α provided the fastest drug release, while SAP3α demonstrated a slowest release. SAP2α was selected for in vivo evaluation based on their balanced DL-α-tocopherol release along with favorable mechanical strength and swelling properties. SAP2α MNs significantly increased skin moisture from 13% to 37% within 8 days, outperforming the control and blank groups. These results show the potential of SA-based hydrogel MNs for transdermal drug delivery for skin rejuvenation and anti-aging. The moisturizing effectiveness of SAP2α MNs suggests their strong clinical potential in dermatology and cosmetic treatments for combating skin aging and dryness.
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