Drug Delivery and Translational Research最新文献

Since the first market authorization of RNA therapies, just eight years ago, the field has witnessed an extraordinary expansion, ranging from hepatic delivery for rare genetic diseases to global-scale vaccination during the COVID-19 pandemic, and now to cutting-edge cancer vaccines and gene editing strategies entering late-stage clinical trials. In parallel, the RNA therapeutics landscape has evolved rapidly, progressing from small interfering RNAs to next-generation and combinatorial RNA modalities. None of these breakthroughs would have been possible without the development of sophisticated RNA delivery technologies capable of navigating complex biological environments, enabling precise cellular targeting, and facilitating efficient intracellular trafficking. In this Editorial Note, we take a step back to reflect on key lessons learned throughout the RNA delivery journey. Featuring insights from leading and experienced voices in the field, this manuscript highlights critical milestones, persistent challenges, and the roles of lipid nanoparticles (LNPs) and polymer nanoparticles (PNPs) as RNA delivery platforms. These experts reflect on the features that have positioned LNPs as the current RNA delivery gold standard, while also exploring the untapped potential and distinctive advantages of polymer-based nanosystems. Collectively, these perspectives underscore a striking truth: we are only beginning to unlock the full therapeutic potential of RNA, and nanomedicine will certainly continue to shape the future clinical translation of RNA-based therapies.

Messenger RNA (mRNA) based therapeutics have emerged as a transformative modality with immense potential for treating infectious diseases, cancer, genetic disorders, and other complex conditions. Despite their promise, clinical translation has been challenged by mRNA's intrinsic instability, rapid degradation, and limited target specificity. The therapeutic value of mRNA lies in its ability to precisely modulate or restore protein expression, offering a versatile platform for personalized medicine. While conventional delivery approaches have yielded modest improvements, the integration of nanotechnology, particularly stimuli-responsive, nanoparticle-mediated systems, represents a breakthrough in overcoming these limitations. These advanced nanocarriers respond to both endogenous physiological triggers (such as pH shifts, redox gradients, reactive oxygen species, enzymatic activity, and hypoxic environments) and exogenous stimuli (including light, ultrasound, magnetic fields, and temperature changes), thereby enabling controlled, site-specific, and temporally regulated mRNA release. This dual responsiveness enhances therapeutic efficacy by improving mRNA stability, bioavailability, and minimizing off-target immune activation. This review highlights the design principles, mechanisms, and therapeutic applications of stimuli-responsive nanocarriers in mRNA delivery. It underscores recent innovations in nanoparticle engineering that address existing challenges and pave the way for next-generation precision medicine. Together, these advancements signal a paradigm shift in targeted mRNA therapy, offering new hope for treating previously intractable diseases.

Injectable hydrogels (IHs) have emerged as versatile biomaterials that enable localized therapy through minimally invasive delivery. Their in situ sol-gel transition supports sustained and targeted release of therapeutics, enhancing patient comfort and reducing dosing frequency. However, clinical translation remains limited due to challenges in achieving controlled degradation, ensuring long-term biocompatibility, scaling production, and meeting regulatory standards. Despite these hurdles, several IH-based formulations are progressing through clinical trials or have reached the market, underscoring their therapeutic potential. This review examines the major translational barriers and highlights recent advances that are accelerating the adoption of IHs in precision and personalized medicine.

Doxycycline (DOXY) is a well-established antibiotic that has recently shown potential in inhibiting matrix metalloproteinase-2 (MMP-2), a key enzyme involved in the progression of abdominal aortic aneurysms (AAA). However, the controlled delivery of DOXY to the aneurysm site, with sustained release and minimal systemic exposure, remains a critical challenge in therapeutic development. To address this, we developed a targeted drug delivery platform based on polymeric nanoparticles (NPs), prepared from water-in-oil-in-water nano-emulsions, encapsulating DOXY and are covalently attached to electrospun ε-poly(caprolactone) (ε-PCL) microfibers. This system was designed to enable local, sustained drug release in the inner wall of aorta while preserving the mechanical properties of the aortic wall. The ε-PCL electrospun microfibers from the patch were first functionalized using oxygen cold plasma treatment, creating free radicals that enabled covalent bonding with chemical groups on the outer layer of DOXY-loaded poly(lactic-co-glycolic acid) (PLGA) NPs. This strategy allowed for robust immobilization of the NPs onto the microfibers surface, forming a composite system capable of localized and controlled drug release over time. Unlike traditional delivery approaches, this method ensures site-specific action of DOXY directly at the aneurysmal tissue, minimizing systemic circulation and reducing off-target toxicity. The platform not only provides a stable drug reservoir but also offers intrinsic biomechanical reinforcement, which is critical in AAA condition. This innovative delivery system represents a significant advance in the localized treatment of vascular disorders. It offers a biocompatible, biodegradable, and precisely targeted therapeutic approach, with potential to reduce the need for surgical intervention and limits the adverse effects associated with systemic drug administration. HIGHLIGHTS: - Novel polymeric Doxycycline loaded PLGA nanoparticles have been developed and result efficacious within hMMP-2 mitigation and collagen degradation in Abdominal Aortic Aneurysm condition. - Doxycycline loaded polymeric nanoparticles were covalently anchored to ε-Poly(caprolactone) electrospun microfibers via cold plasma-induced radical grafting, enabling sustained drug release for over 12 days. - Doxycycline-loaded nanoparticles released from microfibers efficaciously mitigate hMMP-2 in human in vitro models of Abdominal Aortic Aneurysm. - Doxycycline released from drug-coated electrospun ε-Poly(caprolactone) although efficacious does not allows time-control.

The development of advanced topical delivery systems that enhance skin penetration and ensure controlled release of bioactives is a key focus in pharmaceutical research. Semi-solid extrusion 3D printing (SSE-3DP) has emerged as a versatile technology for fabricating topical patches, allowing precise control over internal architecture to tailor release and penetration profiles. This research investigates the integration of niacinamide (Nia) and vitamin A-palmitate (VitA) into printable gelatin-based inks, employing both pre-printing rheological assessments and post-printing structural analyses-scanning electron microscopy (SEM), micro-computed tomography (micro-CT) and mechanical properties (tension and compression). Additionally, the study evaluates how variations in patch internal design affect the release kinetics and penetration profiles of Nia and VitA, utilizing both in vitro (Franz cells and Raman Microscopy, RM) and in vivo quantitative (Confocal Raman Spectroscopy, CRS) methodologies. Results indicated a significant correlation between in vitro and in vivo data. Additionally, RM provided valuable molecular-level insights, making it an effective in vitro tool for investigating skin retention. CRS in vivo highlighted different penetration behaviors: while Nia penetration was strongly influenced by the patch design (porous vs. occlusive: 20 min, 0.074 ± 0.027 mg/cm² and 0.048 ± 0.022 mg/cm²; 40 min, 0.084 ± 0.037 mg/cm² and 0.052 ± 0.038 mg/cm²), particularly after short application times, VitA penetration was highly dependent on the integrity of the skin barrier (normal vs. slightly compromised). Notably, this work introduced the first study to apply quantitative in vivo CRS to evaluate 3D-printed topical systems, highlighting the potential of SSE-3DP as a design-driven strategy for effective and personalized topical delivery.

Laser interstitial thermal therapy (LITT) is a minimally invasive treatment for brain tumors that are recurrent or surgically inaccessible. We developed a murine model of LITT to investigate its effects on tumor burden, immune activation, and delivery of heat-activated therapeutics. We engineered a preclinical LITT system using a 1064-nm laser coupled to a 400-μm fiber-optic probe. Orthotopic gliomas were established in the right frontal cortex of BL6 mice using luciferase-transduced glioma cells. Ten days post-implantation, mice were treated with LITT (0.45 or 0.75 W). Tumor response and blood-brain barrier (BBB) disruption were assessed using bioluminescence imaging (BLI), Evans Blue dye, and histology at 3, 7, and 14 days post-treatment. Immunofluorescence (IF) staining characterized immune cell activation. The distribution of doxorubicin released from intravenously administered Thermodox^® was also evaluated. LITT disrupted the BBB, enabling Evans Blue dye and doxorubicin penetration up to 4 mm from the probe. Tumor burden was reduced by LITT, as shown by decreased hypercellularity on H&E and reduced BLI signal, while sham-treated mice showed tumor progression. A reproducible ablation zone formed at the probe site. IF revealed increased IBA1 + macrophages and T cell infiltration in LITT-treated brains. Thermodox^®-derived doxorubicin distribution correlated with thermal diffusion and matched a Fickian perfusion model. We present a reproducible preclinical model of LITT that enables investigation of tumor ablation, immune modulation, and thermally triggered drug delivery. These findings support the use of LITT as a platform for combinatorial strategies in glioma treatment.

Microneedle (MN) arrays bypass the skin's stratum corneum barrier to deliver drugs directly into the viable tissue. The skin disposition of three types of MNs-dissolvable, degradable and hydrogel-forming, fabricated using different polymers-have been evaluated post-treatment with examples of these MN arrays and then examined by confocal Raman spectroscopy and stimulated Raman scattering (SRS) microscopy. The presence of the polymers was assessed from their characteristic Raman signals. SRS image mosaics were acquired to survey and visualise larger areas of the skin surface. After MN insertion, the skin's spectrum was acquired using confocal Raman spectroscopy at the surface, and at nominal depths of 50 µm, 100 µm, and 150 µm. For dissolvable and degradable MNs, Raman signals from the constituent polymers were detectable in the skin. However, the polymer used to form the hydrogel MNs was not detectable under the experimental conditions used. SRS confirmed that the MN arrays penetrated the skin in a reasonably uniform manner. In summary, polymeric MN insertion into the skin has been visualised using confocal Raman spectroscopy and SRS microscopy. Together, these techniques have the potential to shed light on the spatial and temporal skin disposition of the constituent MN polymers used.

Microneedle patches, which are minimally invasive and have high patient compliance, offer a potential alternative for transdermal drug delivery, particularly in chronic diseases such as osteoporosis, which require consistent long-term therapy. Genistein is an osteoprotective plant-derived isoflavone that suffers from poor aqueous solubility and low bioavailability, thereby limiting its medicinal value. In this study, a genistein-loaded solid lipid nanoparticles integrated with dissolving microneedles was developed for the management of osteoporosis. SLNs were prepared using glyceryl monostearate and Tween 80, and optimized by using a Box-Behnken design. The optimised formulation of SLNs (F3) was incorporated into dissolving microneedles. The developed dissolving microneedles were studied for various characterisations, and they featured uniform geometry, sharp, pointed edges, a drug delivery profile of 69.218 ± 3.64% at 8 h. Its anti-osteoporotic studies were carried out on 6 groups of Wistar albino rats, and studies showed that significant decrease in the creatinine level and osteoclast cells; on the other hand, a substantial increase in total protein, bone weight, hardness, thickness, and trabecular composition. A skin irritation test, which was performed, manifested the biocompatible, dermatologically safe quality of the developed dissolving microneedles. This microneedle platform, coupled with an optimised SLNs carrier, ensures a non-invasive controlled transdermal delivery, maximising genistein's osteogenic potency for the effective management of osteoporosis.

With nearly half of all pregnancies occurring unintended, effective and acceptable contraceptive options remain a global necessity. Though contraceptives with extended durations of action reduce the need for strict daily adherence, thus enhancing compliance and reliability, only one of these methods - the copper intrauterine device (IUD) - prevents pregnancy without administering exogenous hormones. Herein, we demonstrate co-delivery of two nonhormonal contraceptive agents, lactic acid (LA) and glycerol monolaurate (GML), using a next-generation 3D-printed intravaginal ring (IVR). Through alterations in ring properties and drug loading, a range of LA and GML release rates were achieved in vitro, demonstrating the flexibility of the platform technology. Rings elicited sustained release of LA and GML at target release rates over 30 days or longer. Additionally, these studies explored how drugs with different physiochemical properties interact within the IVR matrix and further elucidated IVR drug loading and release mechanisms.