Drug Delivery and Translational Research最新文献

{"title":"Enhanced localized pressure-mediated non-viral gene delivery.","authors":"James E Dixon, Vanessa Wellington, Alaa Elnima, Amelie Savers, Lia A Blokpoel Ferreras, Aveen R Jalal, Hoda M Eltaher","doi":"10.1007/s13346-025-01827-7","DOIUrl":"https://doi.org/10.1007/s13346-025-01827-7","url":null,"abstract":"<p><p>Topically applied therapies must not only be effective at the molecular level but also efficiently access the target site which can be on milli/centimetre-scales. This bottleneck is particularly inhibitory for peptide and nucleic acid macromolecule drug delivery strategies, especially when aiming to target wounded, infected, and poorly perfused tissues of significant volume and geometry. Methods to drive fluid-flow or to enhance physical distribution of such formulations after local administration in accessible tissues (skin, eye, intestine) would be transformative in realizing the potential of such therapeutics. We previously developed a technology termed Glycosaminoglycan (GAG)-binding enhanced transduction (GET) to efficiently deliver a variety of cargoes intracellularly, using GAG-binding peptides and cell penetrating peptides (CPPs) in the form of nanoparticles. Herein, we demonstrate that the most simplistic GET formulation is relatively poor in diffusing into tissue matrix (tested in collagen scaffolds). Changing nanoparticle physicochemical properties can enhance penetration, however the use of a pressure differential, generating fluid-flow significantly enhances effective gene delivery over milli/centimetre scales. We adapted clinically used pressure systems to administer both negative (Negative pressure (NP) wound therapy; NPWT) and positive pressures (PP; Insufflator). Pressure differences generated enhanced distribution, and we were able to show for the first-time localized gene transfer in vitro in cell scaffolds and enhanced transfection of ex vivo skin explants. The ability to simply control intra-tissue localization of gene delivery on milli/centimetre scales using pressure application will facilitate new drug delivery strategies for accessible tissues. Importantly site-specific enhancement of penetration and activity of novel nanotechnologies and gene therapeutics could be transformative for future regenerative medicine strategies.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual acting oxaliplatin (IV) prodrug loaded albumin nanoparticles for safer synergistic anticancer action against triple negative breast cancer.","authors":"Kshitija Abhang, Sayali Dighe, Oly Katari, Vivek Yadav, Sanyog Jain","doi":"10.1007/s13346-025-01833-9","DOIUrl":"https://doi.org/10.1007/s13346-025-01833-9","url":null,"abstract":"<p><p>Owing to faulty DNA damage repair system, triple negative breast cancer (TNBC) exhibits high susceptibility towards DNA damaging drugs such as platinum compounds e.g., oxaliplatin. Nevertheless, the clinical utility of oxaliplatin (OXA) has been constrained due to chemoresistance and chronic toxicities. Hence, to confer systemic inertness, tumor specific delivery, and multifaceted action, a octahedral OXA-CBL prodrug was synthesized using chlorambucil (CBL) as an axial ligand. The combination of OXA and CBL exhibited synergistic anti-cancer action in TNBC cell lines. Further, to potentiate the cellular internalization, targeting efficiency, and in-vivo performance, the synthesized prodrug was loaded into bovine serum albumin nanoparticles (OXA-CBL/BSA-NPs). The prepared nanoparticles had optimal particle size < 200 nm and high drug loading (∼ 5.863 ± 0.16%). As relative to free conjugate, the nanoparticles exhibited amplified cellular internalization and reduced the IC₅₀ in 4T1 (∼ 1.38-fold) and MDA-MB-231 (∼ 1.43-fold) cell line. The anti-cancer study in 4T1-based TNBC model in BALB/c mice demonstrated significantly higher tumor inhibition rate, and reduced tumor burden in OXA-CBL/BSA-NPs treated group. Toxicity assessment revealed no signs of hepato- and/or renal toxicity. Also, nanoparticles exhibited sufficient compatibility with erythrocytes. Overall, delivery of OXA-CBL via virtue of albumin nanoparticles presents safer and efficacious approach to combat TNBC.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of beta and gamma radiation sterilization on growth factor-loaded nanoparticles: an innovative approach for osteoarticular disorders treatment.","authors":"Jorge Ordoyo-Pascual, Sandra Ruiz-Alonso, Idoia Gallego, Laura Saenz-Del-Burgo, Jose Luis Pedraz","doi":"10.1007/s13346-025-01829-5","DOIUrl":"https://doi.org/10.1007/s13346-025-01829-5","url":null,"abstract":"<p><p>The prevalence of various diseases, including osteoarticular conditions, is increasing as the world's population ages. These disorders lead to degeneration of bones and joints, diminishing the quality of life of the geriatric population and imposing a significant economic burden on healthcare systems. The aim of the present study is to sterilize nanostructured lipid carriers (NLCs) loaded with vascular endothelial growth factor 165 (VEGF165) and platelet-derived growth factorBB (PDGF-BB) without compromising their properties to improve osteoarticular disease prognosis. Therefore, two methods of sterilization using ionizing radiation - beta radiation and gamma radiation - and two different doses - 12 kGy and 25 kGy - were investigated. Subsequently, the study evaluated whether the sterilization process had any effect on the nanoparticles and encapsulated growth factors by assessing their physicochemical properties, toxicity, release profiles and bioactivity. The treatment with 12 kGy of beta radiation successfully sterilized the batch of nanoparticles without inducing any changes in the physicochemical properties. In addition, the release profile of VEGF165 remained unchanged, although a slight decrease was observed in the case of PDGF-BB. The biological activity of the growth factors showed a slight decrease, with the most effective concentrations being 5 ng/mL for VEGF165 and 50 ng/mL for PDGF-BB. Taken together, these findings suggest that the nanoparticles loaded with VEGF165 and PDGF-BB can be successfully sterilized while retaining both their properties and biological activity. These nanoparticles may offer a promising new approach for the treatment of osteoarticular diseases by enhancing vascularization and promoting cellular proliferation in the affected tissue.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simvastatin loaded surface-decorated 3D-dendritic mesoporous silica nanoparticles for enhanced antihyperlipidemic activity: in vitro and in vivo appraisal.","authors":"Abdulsalam M Kassem, Elsaied H Barakat, Maged K Elsayad, Sherif E Emam, Tarek M Ibrahim, Ayman Salama, Mohammed Elmowafy, Nabil K Alruwaili, Omar Awad Alsaidan, Mohamed A Abdelgawad","doi":"10.1007/s13346-025-01825-9","DOIUrl":"https://doi.org/10.1007/s13346-025-01825-9","url":null,"abstract":"<p><p>Simvastatin is a potent statin with antioxidant and anti-inflammatory characteristics, often used to treat hyperlipidemia and related cardiovascular disorders. Nonetheless, its therapeutic advantages are limited by poor water solubility and substantial degradation by CYP3A4 enzymes. This research aimed to improve simvastatin's physicochemical characteristics and therapeutic effectiveness by developing 3D-dendritic mesoporous silica nanoparticles as nanocarriers. Dendritic silica nanoparticles were manufactured using a one-pot biphase stratification process and then surface-modified with aminopropyl groups to enhance drug loading and release characteristics. The optimization of loading parameters, such as solvent type, drug-to-carrier ratio, and loading duration, produced dendritic spherical nanoparticles with a uniform size (< 200 nm), a zeta potential of + 21 mV, and a substantial drug loading capacity (> 20%). Characterization verified the conversion of crystalline simvastatin into an amorphous state, promoting improved saturation solubility and demonstrating sustained release via a Fickian diffusion mechanism. In vivo assessments revealed enhanced antihyperlipidemic, antioxidant properties, and considerable protection against oxidative damage in a poloxamer-407-induced hyperlipidemia model. Histological evaluations of liver and aorta tissues demonstrated almost normal morphology, highlighting the safety and usefulness of the nanoparticles. These results emphasized the potential of aminated dendritic silica nanoparticles as an effective platform for enhancing simvastatin therapeutic efficacy.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microemulsion-based formulation of enterocin CC2: a novel antimicrobial solution targeting Streptococcus mutans.","authors":"Zhang Jin Ng, Choon Fu Goh, Ana Masara Ahmad Mokhtar, Rozi Nuraika Binti Ramli, Chee Keong Lee, Joo Shun Tan","doi":"10.1007/s13346-025-01823-x","DOIUrl":"https://doi.org/10.1007/s13346-025-01823-x","url":null,"abstract":"<p><p>Dental caries, driven predominantly by Streptococcus mutans, remains a significant global challenge. Conventional treatments often fall short due to antimicrobial resistance and limited efficacy. Enterocin CC2, a potent bacteriocin, offers a promising alternative but is hindered by stability and delivery challenges. This study pioneers the development of a cutting-edge microemulsion designed to enhance the stability, bioavailability, and antimicrobial potency of enterocin CC2 against S. mutans. A comprehensive screening of 124 formulations was conducted, evaluating thermodynamic stability, cytotoxicity, and antioxidant potential. The optimized formulation underwent rigorous analysis for physicochemical properties, antimicrobial activity, and long-term stability under varied storage conditions. The innovative microemulsion formulation, incorporating 0.5 mg/mL enterocin CC2, 0.5% surfactant blend (Tween 80 + PEG 400, 1:1), and 0.5% oil, demonstrated micro-sized droplets (88.50-92.10 nm), exceptional thermodynamic stability, and robust antimicrobial efficacy. Remarkably, it reduced the time to eradicate S. mutans UKMCC 1019 from 8 h (unformulated) to 5 h, outperforming 0.2% w/v chlorhexidine and 0.5 mg/mL nisin. Stability tests confirmed consistent performance in pH, viscosity, and antimicrobial activity for up to six weeks across various temperatures, with no detectable cytotoxicity. This study introduces a groundbreaking microemulsion formulation that redefines antimicrobial therapy for S. mutans. By leveraging the enhanced stability and rapid action of enterocin CC2, this innovation offers a transformative approach to oral health management, paving the way for next-generation antimicrobial solutions.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local delivery of an adenosine receptor agonist reduces inflammation associated with contact hypersensitivity.","authors":"Elizabeth R Bentley, Stacia Subick, Jake Doran, Julie Kobyra, Stephen C Balmert, Steven R Little","doi":"10.1007/s13346-025-01831-x","DOIUrl":"https://doi.org/10.1007/s13346-025-01831-x","url":null,"abstract":"<p><p>Allergic contact dermatitis (ACD), a T-cell mediated inflammatory skin condition, is prompted by multiple, subsequent exposures to contact allergens (e.g., nickel). Current treatment approaches for ACD include repeated topical application or systemic delivery of immunosuppressants. These treatment strategies have many limitations, including non-specific mechanism of actions and the occurrence of side effects due to their delivery method. For this reason, we developed a novel therapeutic approach that is based upon adenosine (Ado) receptor signaling, a known anti-inflammatory pathway. Specifically, we developed a polymer microparticle-based controlled release system capable of presenting IBMECA (IBMECA-MPs), an Ado receptor agonist, to the local environment. In this study, we first sought to study the immunosuppressive effects of IBMECA on immune cells implicated in the pathogenesis of ACD (e.g., dendritic cells) in vitro. Subsequently, we examined the effects of enhancing adenosine signaling in contact hypersensitivity (CHS), an in vivo model of ACD, through local administration of IBMECA-MPs. We observed that IBMECA-MPs were capable of reducing the inflammatory response associated with CHS by reducing maturation markers of antigen-presenting cells, altering cytokine secretion, and reducing relative frequencies of effector T cell populations. To our knowledge, this is the first demonstration of therapeutic efficacy of IBMECA in CHS, as well as the first proof-of-principle demonstration of IBMECA application in the context of a local drug delivery system. Ultimately, this delivery system has the potential to be adapted for use in other T-cell mediated inflammatory conditions (e.g., transplant rejection), suggesting broader implications of this study.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing the composition of lipid nanoparticles to selectively deliver mRNA to splenic immune cells for anticancer vaccination.","authors":"Mahmoud A Younis, Yusuke Sato, Yaser H A Elewa, Hideyoshi Harashima","doi":"10.1007/s13346-025-01824-w","DOIUrl":"https://doi.org/10.1007/s13346-025-01824-w","url":null,"abstract":"<p><p>Herein, we report a design for lipid nanoparticles (LNPs) that specifically delivers mRNA to splenic immune cells post intravenous administration for potential anticancer vaccination applications. A diverse library of ionizable lipids was screened in vivo, in combination with various helper lipids, where the composition of LNPs was tweaked to control their in vivo performance. The biodistribution of the LNPs was then investigated at both organ and sub-organ levels. Subsequently, the LNPs were recruited to deliver an anticancer mRNA-based vaccine to mice. The in vivo tropism of the LNPs was dramatically affected by the chemical structure of the ionizable lipids in question, where a model lipid, CL15H6, was recognized as displaying high affinity for the spleen. Further optimization of the composition of the LNPs enabled highly efficient and spleen-selective mRNA delivery, where the optimized CL15H6 LNPs demonstrated a high capacity for homing to splenic antigen-presenting cells (APCs). Furthermore, loading the LNPs with a low dose of ovalbumin-encoding mRNA (mOVA), as a model antigen, protected the mice against OVA-expressing tumor challenges and suppressed the tumor growth in tumor-bearing mice by ~ 75%, which was superior to the results of a clinically-relevant formulation. The CL15H6 LNPs proved to be biosafe upon either acute dose escalation or repeated administrations. The novel and scalable platform reported herein is promising for clinical translation as a neoantigen vaccine.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improvement of coronary microcirculation in acute myocardial ischemia rats using a nanoscale carrier SiO₂@PEG loaded with Nicorandil.","authors":"Rui Wang, Yujing Mo, Yingcong Liang, Yuanhui Liu, Zhongchan Sun, Wenting Shang, Ling Xue","doi":"10.1007/s13346-025-01820-0","DOIUrl":"https://doi.org/10.1007/s13346-025-01820-0","url":null,"abstract":"<p><p>Coronary microcirculatory dysfunction, affecting over half of acute myocardial infarction (AMI) patients, correlates significantly with AMI prognosis. Nicorandil is an effective drug that markedly improves coronary microcirculation, but current clinical formulations of Nicorandil exhibit a relatively short half-life and lack cardiac selectivity. We formulated and synthesized a variety of mesoporous silica nanoparticles (MSNs) as a drug carrier for loading and delivering Nicorandil. We performed PEG modification on MSNs to enhance their biocompatibility. The SiO₂@PEG showed good serum stability, maintained a uniform spherical structure with a particle size distribution centered within 200 nm and exhibits good dispersibility. SiO₂@PEG-Nicorandil showed no significant impact on AC 16 cells' viability at concentrations up to 50 µg/mL. SiO₂@PEG-Nicorandil significantly enhanced the viability of AC16 cells under oxidative stress conditions, while concurrently reducing intracellular levels of reactive oxygen species (ROS) and Ca²⁺. For the rat coronary microvascular dysfunction model, the SiO₂@PEG-Nicorandil group demonstrated a greater decrease in thrombus formation and the expression of inflammatory cytokines, outperforming the Nicorandil group. In vivo imaging revealed that within one hour post-injection of SiO₂@PEG-Nicorandil-CY7, a notable increase in CY7 fluorescence intensity was observed in the cardiac region compared to surrounding tissues. Drug concentration measurements demonstrated that Nicorandil maintained a stable concentration in cardiac blood at 48 h in the SiO₂@PEG-Nicorandil group. Taken together, SiO₂@PEG-Nicorandil had exhibited superior cardiac-targeting capabilities and sustained-release properties. Within a specific concentration range, it demonstrated enhanced therapeutic effects in the treatment of coronary microcirculation disorders in rats when compared to conventional Nicorandil formulations.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nano-formulated curcumin uptake and biodistribution in the fetal growth restricted newborn piglet brain.","authors":"Nuo Xu, Julie Wixey, Kirat Chand, Megan Wong, Elizabeth Nance","doi":"10.1007/s13346-025-01830-y","DOIUrl":"https://doi.org/10.1007/s13346-025-01830-y","url":null,"abstract":"<p><p>Fetal growth restriction (FGR) affects 5% to 10% of all pregnancies in developed countries and is the second most leading cause of perinatal mortality and morbidity. Life-long consequences of FGR range from learning and behavioral issues to cerebral palsy. To support the newborn brain following FGR, timely and accessible neuroprotection strategies are needed. Curcumin-loaded polymeric nanoparticles, which have been widely explored for the treatment of cancer, neurological disorders, and bacterial infections, have the potential to prevent and mitigate pathogenic inflammatory processes in the FGR brain. Curcumin is a hydrophobic molecule with poor aqueous solubility and therefore has been incorporated into nanoparticles to improve solubility and delivery. However, curcumin loading in many nanoparticles can be limited to 10% by weight or lower. Here, we first optimize the formulation process of curcumin-loaded polymeric nanoparticles to find a tunable, reproducible, and stable formulation with high curcumin loading and encapsulation efficiency. We establish a curcumin formulation with 39% curcumin loading and > 95% curcumin encapsulation efficiency. Using this formulation, we assessed the biodistribution of polymeric nanoparticles in FGR piglets and normally grown (NG) piglets following different administration routes and evaluated brain cellular uptake. We show a significant amount of nanoparticle accumulation in the brain parenchyma of neonatal piglets as early as 4 h after intranasal administration. Nanoparticles colocalized in microglia, a therapeutic target of interest in FGR brain injury. This study demonstrates the potential of curcumin-loaded nanoparticles to treat neuroinflammation associated with FGR in the newborn.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two-step ultrasonic cavitation controlled delivery of brain exogenous nucleic acids for ischemic stroke using acoustic-cationic-polymeric-nanodroplets.","authors":"Wei Dong, Guihu Wang, Yichao Chai, Wenjuan Li, Shichang Liu, Huasheng Liu, Wenlei Guo, Senyang Li, Xinrui He, Mingxi Wan, Zongfang Li, Yujin Zong","doi":"10.1007/s13346-025-01828-6","DOIUrl":"https://doi.org/10.1007/s13346-025-01828-6","url":null,"abstract":"<p><p>Inefficient and low-precision delivery of exogenous nucleic acids (ENA) severely limits gene therapy on ischemic stroke (IS). Two problems need to be urgently addressed to improve the efficacy of gene therapy; first, the blood brain barrier (BBB) should be open to promote the accumulation of ENA or genetic material carriers in the ischemic brain parenchyma, and second, the efficient delivery of ENA into the ischemic cells. Previous studies applied ultrasonic cavitation either for opening BBB or for inducing sonoporation to deliver genetic materials into cells. However, the effectiveness of the two-step ultrasonic cavitation to deliver ENA in the brain remains unclear, let alone the genetic materials to be controllably delivered into the ischemic brain parenchyma of the IS. This study systematically explored the BBB opening and ENA delivery by the two-step ultrasonic cavitation using artificial acoustic-cationic-polymeric-nanodroplets (ACPNs). The results demonstrated that the first focused ultrasound (FUS), set at parameters of 3.3 MPa, 20 Hz, 200 cycles and 5 s, stimulating intravascular ACPNs cavitation effectively opened BBB to allow nonactivated ACPN extravasation and accumulation into the ischemic brain parenchyma. Then, the extravascular ACPNs enhanced the second ultrasonic cavitation that noninvasively and efficiently controlled ENA delivery to the ischemic cells through sonoporation, particularly applying 3.3 MPa, 60 Hz, 200 cycles and 9 s to control FAM-eNA delivery, and 3.6 MPa, 20 Hz, 200 cycles and 7 s for pEGFP-C1 controlled delivery. Overall, the two-step ultrasonic cavitation represented a potential strategy for IS-targeted ENA controlled delivery.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}