Drug Delivery最新文献

{"title":"Liposome-mediated delivery of a ruthenium-based metallodrug to overcome cisplatin resistance in osteosarcoma.","authors":"Dzohara Murillo, Elena Domínguez-Jurado, Carmen Huergo, Borja Gallego, Paula Díez, Andrea Ferreras, Enol Álvarez-González, Verónica Rey, Mar Rodríguez-Santamaría, Ana S Indurain, Fernando de Andrés Segura, Iván Bravo, Ángel Ríos, Adela A Fernández-Velasco, Iván Fernández-Vega, Carlos Alonso-Moreno, René Rodríguez","doi":"10.1080/10717544.2026.2671485","DOIUrl":"10.1080/10717544.2026.2671485","url":null,"abstract":"<p><p>The treatment of osteosarcoma has remained largely unchanged over the past decades. Its low incidence, predominantly affecting children and young adults, combined with marked biological heterogeneity, poses major challenges to the development of effective therapies, and currently approved regimens often yield variable responses. Additionally, the frequent emergence of drug-resistant phenotypes in these mesenchymal tumors further compromises treatment success. As a result, despite substantial research efforts, patients with osteosarcoma still face a poor prognosis, underscoring the urgent need for improved therapeutic strategies. Alongside doxorubicin and methotrexate, cisplatin is one of the primary first-line chemotherapeutic agents used for osteosarcoma. However, like other cytotoxic drugs, cisplatin is limited by severe systemic toxicity and the development of resistance. In this study, we investigated the antitumor potential of a novel ruthenium organometallic compound, Ru3, and its liposomal encapsulation as a nanomedicine approach to provide a safer and more effective alternative to platinum-based therapy for both cisplatin-resistant and parental osteosarcoma models. <i>In vitro</i>, both free and liposomal Ru3 displayed stronger cytotoxicity than cisplatin in most models, effectively reversing drug resistance. Ru3 formulations also maintained potent activity in 3D osteosarcoma spheroids and selectively targeted cancer stem cell-enriched tumorspheres. <i>In vivo</i>, treatment with liposomal Ru3 in mice bearing cisplatin-resistant xenografts produced superior therapeutic outcomes and was better tolerated than cisplatin, alleviating its systemic toxicity. Overall, these findings support ruthenium-based metallodrugs delivered via liposomes as promising alternatives to platinum-based chemotherapy for osteosarcoma management.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2671485"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13169444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873755","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":"Local application of otoprotective compounds other than sodium thiosulfate to prevent cisplatin-induced hearing loss: a systematic review.","authors":"Amirhossein Masroor, Nienke Streefkerk, Martine Van Grotel, James I Geller, Marc Ansari, Eric Bouffet, Archie Bleyer, Brice Fresneau, Michael Sullivan, Kristin Knight, Per Kogner, Rudolf Maibach, Allison F O'neill, Vassilios Papadakis, Kaukab M Rajput, Penelope R Brock, Gareth J Veal, Alexander E Hoetink, Alwin D R Huitema, Marry M Van Den Heuvel-Eibrink","doi":"10.1080/10717544.2026.2665892","DOIUrl":"10.1080/10717544.2026.2665892","url":null,"abstract":"<p><p>Cisplatin-induced hearing loss (CIHL) in pediatric cancer patients is an irreversible and highly prevalent adverse effect with a devastating impact on quality of life. Sodium thiosulfate (STS) has recently been approved for systemic administration as an otoprotective agent in children. However, implementation of systemic STS has its challenges, and there is currently limited evidence to support local STS for children. This review investigates the potential value of locally administered otoprotective agents other than STS with a focus on future pediatric implementation. We conducted a systematic review on the efficacy and safety of locally applied non-STS otoprotective agents in <i>in vivo</i> settings. This included a summary of investigated drug delivery methods and administration routes. We identified 70 preclinical and eight clinical studies. Agents were categorized based on their biological mechanisms: anti-inflammatory, chemical deactivators, calcium blockers, biologicals, and miscellaneous mechanisms. Preclinical studies investigated 45 different agents. Dexamethasone and <i>N</i>-acetylcysteine were identified as efficacious agents recurrently and progressed to clinical trials. Dexamethasone was investigated in three randomized clinical trials (RCTs) and three non-randomized clinical studies and showed statistically significant but not clinically relevant benefit in two trials. <i>N</i>-acetylcysteine was investigated in two clinical trials and one RCT and was minimally effective in the RCT and in one clinical study. Our review did not identify available studies of local alternative otoprotective agents that could reliably replace systemic STS in terms of safety and efficacy for pediatric patients. Further research on the optimal dosage, delivery method, and timing of otoprotective agents is needed.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"33 1","pages":"2665892"},"PeriodicalIF":8.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13137753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812606","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":"Blood‒brain barrier opening with Golay-coded ultrasound to improve therapeutic consistency in glioblastoma models.","authors":"Seoyun Chang, Taekyu Jang, Hyochul Lee, Minseok Koo, Ok Kyu Park, Seung Hong Choi, Roh-Eul Yoo, Jinhyoung Park","doi":"10.1080/10717544.2025.2592940","DOIUrl":"10.1080/10717544.2025.2592940","url":null,"abstract":"<p><p>Transcranial-focused ultrasound has demonstrated potential for blood-brain barrier (BBB) opening and localized drug delivery to intracranial brain lesions, making it a promising therapeutic strategy for glioblastoma (GBM) treatment. However, consistent drug delivery is hindered by cranial beam distortions, particularly standing-wave formation, when conventional sinusoidal-periodic ultrasound transmission sequences are used. We propose a novel Golay-coded random (Golay-random) ultrasound transmission sequence to mitigate standing wave effects and address this challenge. The efficacy of the Golay-random sequence was validated through computational simulations, which revealed significantly reduced pressure fluctuations compared to that in sinusoidal-periodic sequences. In vivo experiments quantified the BBB opening using gadolinium contrast-enhanced magnetic resonance imaging (MRI). The Golay-random sequence demonstrated effective BBB opening, with BBB permeability-increasing with burst length from 1.25 to 2.50 ms and plateauing at 5.00 ms. In contrast, no consistent correlation between burst length and BBB opening was observed with the sinusoidal-periodic sequence. In GBM mouse models, posttreatment MRI revealed significantly smaller tumor sizes in the group receiving doxorubicin with Golay-random transmission (G-Dox: 3.72 ± 4.34 mm³) compared to those with sinusoidal-periodic transmission (P-Dox: 18.05 ± 11.81 mm³). Optical in vivo imaging corroborated these findings, showing reduced tumor progression in the G-Dox group (4.54 ± 5.67) relative to the P-Dox group (25.17 ± 33.71). These results highlight the Golay-random sequence as a superior alternative to conventional sinusoidal-periodic sequences, offering improved precision and reliability in drug delivery and enhanced therapies for GBM.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2592940"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12679851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667307","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":"Utilization of DOX-Fe complex and RSL3 co-loaded liposomes in ferroptosis-enhanced treatment of triple-negative breast cancer.","authors":"Jinguo Li, Yuhao Zhang, Changyu Shao, Yining Bai, Puxiu Wang, Tianyang Ren","doi":"10.1080/10717544.2025.2592412","DOIUrl":"10.1080/10717544.2025.2592412","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer and is characterized by high invasiveness, rapid recurrence, and poor prognosis. To date, the ferroptosis-combined therapies have exerted their potential in the TNBC treatments via multi-mechanisms. Here, we reported a doxorubicin (DOX)-Fe complex and RSL3 co-loaded liposomes (DOX-Fe/RSL3@LIPs) for ferroptosis-enhanced chemotherapy on TNBC tumors. This nanoformulation performed a uniform spherical structure with a mean particle size of 126.9 nm, a zeta potential of -3.56 mV, and high colloidal stability. The pH-responsive dissociation of DOX-Fe and release of DOX were conducive to drug accumulation in the tumor microenvironment and tumor cells, meanwhile efficiently suppressed free DOX leakage in the blood circulation, potentially reducing the cardiotoxicity of DOX. <i>In vitro</i> cell and <i>in vivo</i> pharmacodynamic studies demonstrated a favorable anticancer effect of the DOX-Fe/RSL3@LIPs on 4T1 tumors by synchronously delivering biologically active DOX, Fe²⁺, and RSL3 to the tumor sites. DOX induced tumor cell death through a dual pathway of apoptosis/ferroptosis, and promoted the H₂O₂ generation. The tumor cell ferroptosis was observably enhanced via supplements of the ferrous ions and H₂O₂, and RSL3-derived GPX4 inhibition to severely destroy the oxidation balance in cells. In this paper, the DOX-Fe/RSL3@LIPs have exerted a synergistic anticancer effect on TNBC by combining ferroptosis and conventional chemotherapy, and made a meaningful exploration of new strategies for TNBC therapy.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2592412"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12679844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667594","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":"Modeling the synergistic enhancement of drug permeation by a dual-microbubble system under ultrasonic excitation.","authors":"Yingjie Li, Jiwen Hu, Yunsu Wang, Qinlin Li, Youxin Chen","doi":"10.1080/10717544.2025.2597621","DOIUrl":"10.1080/10717544.2025.2597621","url":null,"abstract":"<p><p>The high selectivity of the vascular endothelium, exemplified by the blood-brain barrier (BBB), provides critical protection to tissues against harmful substances; however, it also severely restricts the targeted delivery of therapeutic agents, particularly large molecule drugs. Ultrasound-mediated microbubble cavitation has emerged as a promising strategy for enhancing drug delivery. However, conventional single-microbubble systems suffer from limitations, including uneven energy distribution and suboptimal permeabilization efficacy. Moreover, the synergistic mechanisms underlying dual-microbubble interactions within the microvasculature remain poorly understood. In this study, we developed a coupled two-microbubble fluid-solid system (TMFSS) model utilizing the finite element method to simulate the dynamic behavior of dual microbubbles within blood vessels under ultrasonic excitation. Our investigation focused on key parameters-including microbubble spacing, acoustic pressure amplitude, microbubble size, and shear-thinning blood rheology-and their effects on microbubble oscillation, microstreaming, vascular wall stress, and endothelial permeability. The results demonstrate that, compared with single-microbubble systems, the ultrasound-assisted TMFSS significantly enhances drug permeability. This synergistic permeabilization effect strongly depends on the acoustic parameters, blood viscosity, microbubble size, and spatial distribution. Our study quantitatively elucidates the structure‒activity relationship between TMFSS dynamics and drug penetration efficiency and presents a parameter optimization strategy for the precise modulation of vascular endothelial permeability.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2597621"},"PeriodicalIF":8.0,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12687900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145700013","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":"Enhancing GSDME-induced pyroptosis through low-dose doxorubicin/biflavonoid derivative co-loaded nanodisc in hepatocellular carcinoma.","authors":"Yang Wang, Yanan Fu, Meiying Wu, Haoqiang Wan, Xinchun Chen, Lanlan Ge, Chenyan Shi, Yangfan Li, Xiaobin Zeng, Tianqi Wang","doi":"10.1080/10717544.2025.2587034","DOIUrl":"10.1080/10717544.2025.2587034","url":null,"abstract":"<p><p>The chemotherapeutic drug doxorubicin (DOX) has been demonstrated to trigger pyroptosis in tumor cells at exceptionally high concentrations. Nevertheless, the administration of DOX at suprapharmacological doses could cause acute off-target cytotoxicity and severe adverse effects. Herein, a biflavonoid derivative, F24, was found to improve the sensitivity of hepatocellular carcinoma (HCC) cells to low-dose DOX and reduce the adverse effects of DOX. We demonstrated that F24 synergized with low-dose DOX to increase pyroptosis and autophagy in HCC cells through dual-target CDK6 inhibition/p53 activation at a proper ratio. To achieve this synergistic effect, nanodiscs with large hydrophobic cavities were selected to codeliver the low-dose hydrophobic drugs DOX and F24 (DOX-F24@Nanodisc, DF@N), which improved the tumor accumulation of the two drugs and ensured precise drug ratio integrity within the tumor cells. DF@N can trigger gasdermin-E (GSDME)-based pyroptosis in tumor cells, accompanied by the cleavage of caspase-3. Strikingly, knocking out GSDME or caspase-3 redirected DF@N-driven cellular death from the pyroptosis pathway to the apoptotic pathway. Furthermore, DF@N administration suppressed tumor growth and activated pyroptosis in a Huh7 mouse xenograft tumor model. Overall, F24 was found to induce autophagy by targeting CDK6 and had a synergistic effect on DOX-induced pyroptosis. These results indicate that the pyroptosis-induced DF@N nanodisc system provides an effective and secure therapeutic strategy for treating HCC.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2587034"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12646095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145586556","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":"Photosensitive composite nanoparticles adsorbing p-sh<i>BLM</i> for the synergistic therapy of neuroblastoma.","authors":"Xuelian Luo, Xiaohan Wu, Haifeng Ai, Chunrong Li, Hanghang Jiang, Conghui Wang, Jielin Liu, Song Xiao","doi":"10.1080/10717544.2025.2585608","DOIUrl":"10.1080/10717544.2025.2585608","url":null,"abstract":"<p><p>Photodynamic therapy (PDT) represents a promising noninvasive modality for the selective targeting of tumors. However, its clinical utility is often constrained by the aggregation-induced quenching of photosensitizers and suboptimal reactive oxygen species (ROS) generation. In contrast, gene therapy has exhibited potent antitumor efficacy through the specific silencing of oncogenic targets. In this study, we developed a cationic photosensitizer-based nanocarrier, PEI-PEG-PpIX, designed to deliver the shRNA-<i>BLM</i> plasmid (p-sh<i>BLM</i>). The PEI-PEG-PpIX/p-sh<i>BLM</i> complex demonstrated a threefold increase in ROS production compared to free PpIX, along with a 57.5% enhancement in transfection efficiency. When this method was combined with photodynamic therapy for the treatment of neuroblastoma, the system significantly suppressed tumor cell proliferation, resulting in an 83.67% tumor growth inhibition rate in murine models. This outcome effectively demonstrates the synergistic integration of gene therapy and photodynamic therapy. Furthermore, the multifunctional nature of this platform enables real-time tumor imaging, thereby facilitating image-guided diagnosis and therapeutic monitoring. Overall, this strategy presents a noninvasive, efficient, and targeted approach to cancer treatment, offering valuable insights for future translational applications.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2585608"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12716475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721858","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":"Targeted strategy by curcumin and tideglusib biomimetic nano-systems alleviates oxidative stress and inflammation under ischemic stroke.","authors":"Jiajia Li, Yiliang Yang, Meng Lin, Yitian Du, Yiwei Peng, Yu Zhou, Datong Gao, Yanxia Zhou, Xinru Li, Xianrong Qi","doi":"10.1080/10717544.2025.2585599","DOIUrl":"10.1080/10717544.2025.2585599","url":null,"abstract":"<p><p>Ischemic stroke represents one of the leading causes of disability and death worldwide. Neuroprotection aimed at mitigating oxidative stress and inflammation is crucial for improving the prognosis of patients. However, the inadequate accumulation of drugs at the ischemic site significantly restricts their clinical efficacy. We found that platelet membrane (PLTM)-biomimetic nanosystems loaded with curcumin (Cur@PLTM) and tideglusib (Tid@PLTM) actively targeted the ischemic brain and facilitated transcytosis into the ischemic parenchyma via caveolin-dependent transcytosis, mimicking the recruitment of platelets in damaged cerebral vessels. This represented the first application of tideglusib nanoformulations in treating ischemic stroke, further demonstrating that the therapeutic effects were associated with M2 microglia regulation. Additionally, Cur@PLTM and Tid@PLTM synergistically scavenged reactive oxygen species (ROS) and promoted the secretion of neuroprotective cytokines via redox and cellular regulatory mechanisms to mitigate ischemia/reperfusion (I/R) injury. Overall, this platelet membrane-biomimetic nanosystem offers a prospective strategy for targeted brain delivery and combined treatment through antioxidative and anti-inflammatory approaches against ischemic stroke.</p>","PeriodicalId":11679,"journal":{"name":"Drug Delivery","volume":"32 1","pages":"2585599"},"PeriodicalIF":8.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12667299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145602991","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":"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}