Drug Delivery最新文献

{"title":"Comparative analysis of metabolome and transcriptomes to explore the inhibited influence of sonodynamic therapy combined with lonidamine on hepatocellular carcinoma.","authors":"Haoyan Tan, Huimin Tian, Yichi Chen, Bolin Wu, Wen Cheng, Haitao Shang","doi":"10.1080/10717544.2025.2593600","DOIUrl":"10.1080/10717544.2025.2593600","url":null,"abstract":"<p><p>Sonodynamic therapy (SDT) has emerged as a promising approach for treating hepatocellular carcinoma (HCC) by combining sonosensitizers with low-intensity ultrasound. However, SDT alone could not achieve satisfactory results. Here, we developed novel nanobubbles loaded with hematoporphyrin monomethyl ether (HMME@NBs) and evaluated its therapeutic potential in combination with the glycolytic inhibitor lonidamine (LND) against HCC. The HMME@NBs was successfully prepared with particle size of 410.58 ± 20.07 nm and zeta potential at -8.38 ± 1.12mV. The encapsulation efficiency and loading efficiency of HMME was 80.6% and 7.12%, respectively. Both <i>in vitro</i> and <i>in vivo</i> studies demonstrated that while SDT and LND monotherapies inhibited the growth of HepG2 cells and xenograft tumors in nude mice, the combination therapy exhibited the most significant inhibitory effect. Multi-omics analysis of tumor tissues revealed substantial alterations in metabolites and gene expression, with key pathways such as glutathione metabolism implicated in the treatment response. Our findings highlight the enhanced antitumor efficacy of HMME@NBs-mediated SDT combined with LND, supported by mechanistic insights from transcriptomic and metabolomic profiling. This synergistic strategy holds great potential for HCC treatment.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2593600"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12677030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145660699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifunctional self-emulsifying drug delivery system: an efficient strategy for oral delivery of therapeutic peptides and proteins.","authors":"Guofei Li, Changyu Shao, Yuhao Zhang, Jinguo Li, Puxiu Wang, Tianyang Ren","doi":"10.1080/10717544.2025.2579137","DOIUrl":"10.1080/10717544.2025.2579137","url":null,"abstract":"<p><p>Oral delivery is the most preferred route for accessing bioactive peptides and proteins for disease treatment from the patient's viewpoint. However, this is a great challenge because orally administered peptides and proteins are susceptible to the harsh gastrointestinal (GI) environment, various metabolic enzymes, and thiol/disulfide exchange reactions, and they cannot permeate the intestinal mucus and epithelial barriers. The self-emulsifying drug delivery system (SEDDS) has recently gained prominence because of its potential in the oral delivery of peptides and proteins. Stable payloads of hydrophilic proteins can be achieved in SEDDSs using feasible lipidization techniques, especially hydrophobic ion pairing. Upon entrapment in oily droplets derived from SEDDSs, protein drugs can be protected against enzymatic degradation and thiol/disulfide exchange reactions in the GI tract. After optimizing functional excipients and developing an efficient combination strategy, SEDDS droplets exhibit high mucus and membrane permeability and further enhance drug absorption and transport. The desired oral bioavailability and therapeutic effects of peptide and protein drugs could be achieved <i>in vivo</i>. This review presents the progress in the development of multifunctional SEDDSs for oral peptide and protein delivery. However, with the introduction of more novel multifunctional auxiliary agents and complicated structures to new-generation SEDDSs, more work is needed to identify the effects of excipients in the optimized combination and increase our knowledge of the fate of the excipients and the nanocarrier during absorption and transport. This knowledge will facilitate the future development of multifunctional SEDDSs for the oral application of therapeutic peptides and proteins.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2579137"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12697275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy, safety, and patient-centered outcomes of needle-free injectors versus insulin pens in diabetes management: a comprehensive meta-analysis.","authors":"Jing Wang, Xinhao Chen, Zhili Ge, Yingran Xia, Zixiang Tang, Zehao Sun, Lijing Jiao, Jing Zhou, Lihui Zhang, Zhansheng Zhao","doi":"10.1080/10717544.2025.2597906","DOIUrl":"10.1080/10717544.2025.2597906","url":null,"abstract":"<p><p>To evaluate the comparative effectiveness, safety, and patient acceptance of needle-free injectors and insulin pens through a meta-analysis. A thorough literature search was performed across multiple databases, including CNKI, the Weipu Database, the Wanfang Database, PubMed, Embase, and The Cochrane Library for randomized controlled trials (RCTs) on the use of needle-free injectors and insulin pens in diabetes treatment, with a time frame from database inception until June 2024. Five researchers carefully screened the literature in accordance with the inclusion and exclusion criteria, assessed study quality with validated tools and conducted the meta-analysis using RevMan 5.4. This study included 22 publications encompassing 22 studies, involving a total of 2,580 patients, with 1,290 in the needle-free group and 1,290 in the insulin pen group. The findings suggest that needle-free injectors were superior to insulin pens in improving treatment efficacy, local adverse reactions, and increasing patient acceptability, with statistically significant differences. However, no significant variations were observed in continuous glucose monitoring. Needle-free injectors can improve certain aspects of glycemic control, such as reducing HbA1c, FPG, and 2hPPG; improve local adverse reactions and increase patient acceptability. However, improvements in glycemic variability metrics were not statistically significant, indicating that further research is needed to fully assess their long-term safety and therapeutic effectiveness. In terms of systemic safety, the risk of hypoglycemia in the needle-free group was not significantly different from that in the needle group (<i>P</i> = 0.14). Additionally, our publication bias analysis revealed potential biases in the outcomes related to hypoglycemia and insulin dosage.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2597906"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12704122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotechnology-based targeted regulation of NLRP3 Inflammasome: therapeutic strategies and clinical application prospects in inflammatory diseases.","authors":"Xuan Zhao, Zhikai Xu, Dongfang Wang, Tonghan Li, Ligang Xu, Zhanfei Li, Xiangjun Bai, Hao Zhu, Yukun Liu, Yuchang Wang","doi":"10.1080/10717544.2025.2580730","DOIUrl":"10.1080/10717544.2025.2580730","url":null,"abstract":"<p><p>The NLRP3 inflammasome plays a critical role in the onset and progression of various inflammatory diseases, making targeting its activation an important research direction for treating these conditions. Nanotechnology can effectively inhibit the activation of the NLRP3 inflammasome through several mechanisms, such as scavenging reactive oxygen species (ROS), regulating calcium ion flux, and stabilizing mitochondrial function, thereby alleviating inflammation and promoting tissue repair. Studies have demonstrated that nanomaterials exhibit promising anti-inflammatory effects in animal models, showing broad application potential, particularly in the treatment of conditions such as atherosclerosis, diabetes, and Alzheimer's disease. However, the clinical translation of nanotherapy still faces numerous challenges, including issues related to material biocompatibility, long-term safety, targeting efficiency, and controlled drug delivery. Future research should integrate targeting ligands, responsive materials, and multifunctional nanoplatforms to enhance the specificity and efficacy of treatments while minimizing side effects. Additionally, the prospects of nanotechnology in personalized treatment and clinical applications are substantial, necessitating further integration of basic research with clinical validation to expedite the clinical translation of NLRP3-targeted nanomedicines.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2580730"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12677039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145660759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanomaterial-mediated multidimensional regulation of the bone microenvironment: a precise therapeutic strategy for bone metabolic imbalance.","authors":"Chengyan Guo, Chenyu Zhu, Wenjing Li, Jun Zou, Lingli Zhang","doi":"10.1080/10717544.2025.2595324","DOIUrl":"10.1080/10717544.2025.2595324","url":null,"abstract":"<p><p>With the advancement of global population aging, the incidence of skeletal diseases (e.g. osteoporosis, fractures, and osteoarthritis) in clinical diagnosis increases and poses a serious threat to human health. Skeletal diseases usually occur as a result of disturbed cellular metabolism in a specific period or environment. The bone microenvironment, as an important physiological environment of bone tissue, consists of various cell types, and cell-cell interactions play a decisive role in the biological behavior and metabolic regulation of bone cells. Disorders of the bone microenvironment can exacerbate bone diseases. Conventional therapeutic for skeletal diseases often suffer from poor efficacy, low targeting, and side effects. Therefore, a new therapeutic strategy should be developed urgently to improve the existing deficiencies. With the continuous advancement of nanomedicine, the application of nanomaterials provides new research perspectives and application value for the treatment of skeletal diseases. With their unique physicochemical properties, nanomaterials can directly or indirectly mediate the bone microenvironment to regulate the bone metabolic process through self-regulation, drug carriers, and in vivo scaffolds. All the above strategies are extensively explored in this study. In this paper, we systematically summarize the nanomaterials currently used in the clinical treatment of bone diseases and discuss the application strategies of nanomaterials to regulate the bone microenvironment and thus bone metabolism. Moreover, we evaluated the challenges faced by nanomaterials in the clinical treatment of bone diseases. We aim to provide basic theories and new perspectives for the design and development of novel nanomaterials for improved clinical applications.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2595324"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12683752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a novel alpha7-nicotinic acetylcholine receptor-selective cell-penetrating peptide for intracellular cargo transport.","authors":"Lahra Weber, Brittany C V O'Brien, Maegan M Weltzin","doi":"10.1080/10717544.2025.2587378","DOIUrl":"10.1080/10717544.2025.2587378","url":null,"abstract":"<p><p>Cell membranes present barriers to the intracellular delivery of therapeutic agents. This impediment is frequently exacerbated by the hydrophobic characteristics of many such molecules, ultimately reducing the efficiency of their cellular uptake and therapeutic effectiveness. Therapeutics are being created that exploit natural bypass mechanisms by forming complexes with cell-penetrating peptides (CPPs) derived from viruses. However, current CPPs lack the ability to selectively target precise cellular macromolecules. As a result, they are distributed broadly and cause off-target side effects. Neurotropic CPPs derived from the rabies virus glycoprotein (RVG) can access the brain by binding to plasma membrane targets, including, but not exclusively, nicotinic acetylcholine receptors (nAChRs). To overcome this barrier of minimal target selectivity, we designed several chimeric peptides composed of regions from the RVG and <i>α</i>-bungarotoxin, an α7 subtype-selective protein. Using human nAChRs expressed in <i>Xenopus laevis</i> oocytes, we screened the selectivity of our peptides using two-electrode voltage clamp electrophysiology. We identified a peptide with improved α7 nAChR subtype selectivity and apparent potency compared to the control RVG peptide. Using mammalian Neuro-2a cells, we demonstrated that our peptide depends on α7 nAChR plasma membrane expression to internalize and carry small-molecule payloads into neuronal-like cells without significant cytotoxic effects. Our novel α7 nAChR subtype-selective CPP may be useful in research applications requiring cargo delivery. Translationally, our α7 nAChR-selective CPP holds potential to be a dual drug delivery system to transport cargo into the brain for the treatment of neurological diseases.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2587378"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12667308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145631517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aptamer-mediated liver-targeted curcumin delivery system based on tetrahedral framework nucleic acids for NAFLD.","authors":"Shaoyun Chen, Yuchen Liu, Siying Ma, Lin Chen, Liping Zhou, Jiawen Wang, Yingying Huang, Zhiling Yu, Xiaobing Dou","doi":"10.1080/10717544.2025.2576222","DOIUrl":"10.1080/10717544.2025.2576222","url":null,"abstract":"<p><p>Curcumin is renowned for anti-inflammatory, antioxidant and hepatoprotective effects, and has been implicated in the amelioration of obesity and diabetes. Notwithstanding its considerable therapeutic potential, the clinical utility of curcumin is hampered by its suboptimal bioavailability, due to poor aqueous solubility and chemical instability. Consequently, the development of strategies to enhance the aqueous solubility, stability, and ultimately, the bioavailability of curcumin has been a focal point of intense research. This study harnessed tetrahedral framework nucleic acids (tFNAs), a relatively simple DNA nanostructure, to encapsulate curcumin. Meanwhile, novel aptamers for liver-specific targeting were acquired by SELEX (Systematic Evolution of Ligands by Exponential Enrichment) method. By capitalizing on the unique properties of aptamers and tFNAs, an aptamer-mediated liver-targeted curcumin delivery system was constructed, with the goal of providing a more efficacious therapeutic approach for non-alcoholic fatty liver disease (NAFLD). This innovative delivery platform has not only markedly improved the solubility and stability of curcumin but has also significantly bolstered its therapeutic efficacy in the context of NAFLD. This research not only offers a novel approach for the delivery of curcumin but also presents a new therapeutic modality for NAFLD. Moreover, the implications of this research extend beyond curcumin, offering a blueprint for the liver-targeted delivery of other drug molecules.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2576222"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12604106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145481124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breakthroughs of ultrasound-targeted microbubble destruction in treating myocardial ischemia-reperfusion injury: from angiogenesis regulation to precise inflammation suppression.","authors":"Wei Feng, Pingping He, Zhimin Wang, Weishuai Li","doi":"10.1080/10717544.2025.2594555","DOIUrl":"10.1080/10717544.2025.2594555","url":null,"abstract":"<p><p>Myocardial ischemia-reperfusion injury (MIRI), a frequent complication in acute myocardial infarction (AMI) treatment, arises from complex mechanisms including oxidative stress, inflammation, and mitochondrial dysfunction, which impair myocardial repair and recovery. Current therapies for MIRI offer limited efficacy and raise safety concerns, highlighting the need for innovative and precise treatment strategies in cardiovascular research. Ultrasound-targeted microbubble destruction (UTMD) is a promising therapeutic approach that enhances drug delivery precision to the myocardium. By utilizing ultrasound cavitation and nanodrug delivery, UTMD overcomes microvascular barriers, significantly improving drug bioavailability and therapeutic outcomes. It has demonstrated potential in modulating the hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway to promote angiogenesis and enhance myocardial perfusion. In addition, it inhibits NOD-like receptor protein 3 (NLRP3) inflammasome activation, thereby reducing inflammatory responses and protecting the myocardium from reperfusion damage. The integration of radiomics and artificial intelligence (AI) further advances MIRI diagnosis and treatment. Real-time monitoring of myocardial blood flow and microcirculatory perfusion, combined with AI-driven image analysis, enables accurate assessment of myocardial injury and therapeutic efficacy, supporting personalized and precise therapy. Moreover, multi-omics technologies-such as single-cell RNA sequencing, proteomics, and metabolomics-combined with UTMD provide deeper insights into its therapeutic mechanisms, laying a robust foundation for clinical translation. This review summarizes recent progress in UTMD-based therapies for MIRI, emphasizing their roles in angiogenesis, immune regulation, precision diagnostics, and multi-omics analysis. It highlights new perspectives for future research and clinical applications in the management of MIRI.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2594555"},"PeriodicalIF":8.0,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12697267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A surrogate barrier model for high-throughput blood-brain barrier permeability prediction: integrating LLC-PK1-MOCK/MDR1 Cells and lysosomal trapping correction.","authors":"Juanwen Hu, Xue Jiang, Cong Li, Qiannan Zhang, Xia Wu, Wenpeng Zhang, Xiaomei Zhuang","doi":"10.1080/10717544.2025.2585612","DOIUrl":"10.1080/10717544.2025.2585612","url":null,"abstract":"<p><p>To mitigate risks in central nervous system (CNS) drug development, we established a high-throughput in vitro blood-brain barrier (BBB) model using LLC-PK1-MOCK and LLC-PK1-MDR1 cells in a Transwell system, aiming to replicate in vivo brain distribution and elucidate permeability mechanisms. Model integrity was assessed via transepithelial electrical resistance (TEER) and efflux functionality using control drugs (atenolol, digoxin). Bidirectional transport studies of 41 compounds quantified permeability (P_app), efflux ratios (ER), and recoveries, while in vivo brain distribution parameters (K_{<i>p</i>,uu,brain}) were derived from literature and rat studies. The model demonstrated critical BBB features: tight junction integrity (TEER > 70 Ω·cm²), <i>P</i>-gp efflux activity (digoxin ER = 5.10 ~ 17.12), and discrimination of passive diffusion (63.41% of drugs) from transporter-mediated mechanisms (19.5% <i>P</i>-gp substrates). A training set of 20 randomly selected drugs revealed a robust correlation between MDR1-derived P_app(A-B) and K_{<i>p</i>,uu,brain} (R = 0.8886), with the remaining 21 compounds validating predictive accuracy (≤2-fold error). Four alkaloids exhibiting low recovery (<80%) due to lysosomal trapping were corrected using Bafilomycin A1, aligning their permeability with in vivo outcomes. These results position the LLC-PK1-MOCK/MDR1 model as a reliable surrogate tool for early CNS drug screening, enabling rapid prioritization of candidates based on BBB penetration potential. Its integration into preclinical workflows promises to accelerate the development of therapeutics for neurological disorders.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2585612"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12667295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145631526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcranial ultrasound combined with intravenous metformin-loaded oxygenated microbubbles attenuates noise-induced hearing loss in mice.","authors":"Ai-Ho Liao, Chih-Hung Wang, Lin-Yi Chou, Yu-Chan Hung, Yi-Chun Lin, Ho-Chiao Chuang, Kuo-Hsing Ma, Hao-Li Liu, Jehng-Kang Wang, Cheng-Ping Shih","doi":"10.1080/10717544.2025.2576220","DOIUrl":"10.1080/10717544.2025.2576220","url":null,"abstract":"<p><p>Noise-induced hearing loss (NIHL) involves a biphasic pathophysiology. Intense noise exposure causes immediate cochlear vasoconstriction and ischemia, leading to transient hypoxia. Subsequent reperfusion triggers excess reactive oxygen species (ROS) production, resulting in oxidative stress and hair cell injury. This study therefore developed two oxygenated albumin microbubble (OMB) formulations-ionic-bond metformin-coated (iMet-OMBs) and covalent-bond metformin-encapsulated (cMet-OMBs)-and combined them with transcranial ultrasound (US) to enhance targeted delivery to the cochlea. This approach aims to provide transient oxygen supplementation while simultaneously reducing ROS-mediated injury. Microbubbles were characterized for morphology, oxygen loading, and metformin content. Based on their superior stability and drug-loading profile, cMet-OMBs were selected for <i>in vivo</i> evaluation. In a mouse NIHL model, animals were administered cMet-OMBs systemically via retro-orbital injection, followed by US triggering over the temporal bone. Auditory brainstem response (ABR) thresholds, cochlear oxygen tension, and outer hair cell (OHC) survival were assessed. US-mediated cMet-OMBs rupture transiently increased intracochlear oxygen tension, counteracting early hypoxia after noise exposure. Metformin released from cMet-OMBs attenuated ROS production through mitochondrial complex I inhibition and antioxidant pathway activation. Mice treated with cMet-OMBs + US showed significantly lower ABR threshold shifts and better OHC preservation compared with controls. This dual-action strategy combines transient oxygen supplementation from OMBs with sustained antioxidant protection from metformin. While oxygen delivery raises intracochlear oxygen tension, metformin suppresses ROS generation through mitochondrial complex I inhibition and AMPK/Nrf2 activation. This controlled, US-triggered release achieves net cochlear protection against NIHL without excessive oxidative burden.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2576220"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12599344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145451340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}