Drug Delivery and Translational Research最新文献

{"title":"Exploring topical atorvastatin hyalurosomal gel as an adjuvant for reducing systemic corticosteroid dosage: a randomized clinical trial in severe oral lichen planus patients.","authors":"Mahitab Elsayed, Aya Essawy, Radwa M Ismail, Yasmine Gamil, Mohamed G Hamed, Dalia Elsabaawy, Eman Abdelhakeem, Doaa Hegazy, Radwa M A Abd-Elal","doi":"10.1007/s13346-025-01956-z","DOIUrl":"10.1007/s13346-025-01956-z","url":null,"abstract":"<p><p>Oral lichen planus (OLP) is a chronic inflammatory disorder with limited topical treatment options and long-term corticosteroid dependency. This study investigates a novel atorvastatin-loaded hyalurosomal gel (ATV-Hyalugel) as a topical adjuvant to reduce systemic corticosteroid use in severe OLP. The objective of the study is to develop, optimize, characterize ATV-Hyalugel and evaluate its clinical efficacy in a randomized controlled clinical trial. ATV-loaded hyalurosomes (ATV-HAs) were prepared via thin-film hydration and optimized using an I-optimal mixture design (independent variables: phospholipid, Tween 80, and hyaluronic acid; responses: entrapment efficiency (EE%), particle size (PS), and zeta potential (ZP). The optimal formulation was incorporated into a chitosan gel, which was characterized for its pH, rheological behavior, and in-vitro drug release. Four weeks randomized controlled trial (n = 90) compared: group one received standard prednisolone (40 mg/day) while group two received half-dose prednisolone (20 mg/day) in combination with ATV-Hyalugel (topically, three times daily). Pain and ulcer scores were recorded weekly. Between-group comparisons were performed using the Mann-Whitney U test (non-parametric; α = 0.05), and within-group improvement from baseline to Week 4 was assessed using the Kruskal-Wallis test. Optimized ATV-HAs demonstrated high EE% (79.1 ± 0.4%), uniform PS (221.2 ± 5.1 nm), and stable ZP (-31.6 ± 0.2 mV). ATV-Hyalugel exhibited mucosa-compatible pH (6.48 ± 0.2), pseudoplastic rheology, and a sustained release profile dominated by diffusion-driven kinetics. Clinically, group two achieved therapeutic equivalence to group one by Week 2 (p > 0.05), despite receiving 50% less corticosteroid. Both groups showed significant symptom reduction from baseline to Week four (p < 0.0001, Kruskal-Wallis). No adverse events were reported with ATV-Hyalugel. ATV-Hyalugel enables a 50% corticosteroid dose reduction while maintaining clinical efficacy. Its favorable release kinetics and safety profile support its use as an innovative adjuvant therapy for severe OLP.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"1495-1516"},"PeriodicalIF":5.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isolation of bacterial extracellular vesicles from raw samples using a portable microstructured electrochemical device.","authors":"Valeria Mantella, Siiri Bienz, Finn Brigger, Edouard Baulier, Marie Ramus, Nicole Zoratto, Steffen Honrath, Kumar Naresh, Sibilla Sander, Jörn Dengjel, Renato Zenobi, Vadim Krivitsky, Jean-Christophe Leroux","doi":"10.1007/s13346-025-01954-1","DOIUrl":"10.1007/s13346-025-01954-1","url":null,"abstract":"<p><p>Bacterial extracellular vesicles (EVs) are nanosized vesicles released by both Gram-negative and Gram-positive bacteria, playing critical roles in microbial communication, host-pathogen interactions, and immune modulation. Despite their significance in research and clinical applications, conventional isolation methods, such as ultracentrifugation (UC), are often slow, labor-intensive, and susceptible to contamination. In this study, we evaluated a novel portable microstructured electrochemical device (PMED) designed for rapid and selective bacterial EV isolation directly from biological samples. Using immunoaffinity-based capture and voltage-triggered release, the device-isolated EVs from Gram-negative Escherichia coli (E. coli), Gram-positive Lactobacillus fermentum (Lb. fermentum) culture supernatants and from urine samples spiked with E. coli , showing superior purity compared to UC. Characterization through nanoparticle tracking analysis (NTA), dynamic light scattering (DLS), and Western blot confirms enhanced selectivity and reduced contaminants. Functional assays demonstrated that device-isolated Lb. fermentum EVs selectively activated Toll-like receptor 4 (TLR4) without triggering TLR2, unlike UC-isolated EVs, suggesting a more refined immunomodulatory effect. These findings highlight the device's translational potential for EV-based diagnostics, particularly for noninvasive urinary tract infection detection, and its broader applications in studying bacterial communication and immune regulation.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"1479-1494"},"PeriodicalIF":5.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neratinib-loaded solid lipid nanoparticles in dissolvable microneedles for enhanced transdermal breast cancer therapy.","authors":"Saraisam Kishor Kumar Singha, Venkatesh Dinnekere Puttegowda, Yousef Al-Ebini, Mohamed Rahamathulla, Joysa Ruby Joseph, Ajay Pankajbhai Lunagariya, Mohammed Jafar, Syeda Ayesha Farhana, Manjunatha Panduranga Mudughal, Gowdru Vishwanath Nahusha, Mohammed Muqtader Ahmed","doi":"10.1007/s13346-025-01962-1","DOIUrl":"10.1007/s13346-025-01962-1","url":null,"abstract":"<p><p>Neratinib, an FDA-approved drug for breast cancer, faces challenges such as poor solubility, limited permeability, and adverse side effects. To address these issues, we developed dissolving microneedles incorporating Neratinib-loaded solid lipid nanoparticles (SLNs) to enhance transdermal delivery and minimize systemic toxicity. SLNs were formulated via hot homogenization using glyceryl monostearate as the lipid matrix and were evaluated for particle size, drug entrapment efficiency, drug loading, and stability. The optimized formulation (F7) exhibited a particle size of 209.4 nm and 87.57% entrapment efficiency. SLNs were integrated into microneedles using a micro-molding technique. Characterization included IR spectroscopy, scanning electron microscopy, mechanical strength, and insertion ability. Ex vivo studies on porcine skin demonstrated 80.71 ± 1.43% cumulative drug release over 24 h, confirming effective skin penetration. In vitro cytotoxicity on MCF-7 breast cancer cells showed greater efficacy of the SLN formulation over free Neratinib, with lower IC50 values (55.965 vs. 66.568 µg/mL), indicating enhanced cellular uptake and sustained release. The findings support dissolvable microneedles loaded with Neratinib-SLNs as a promising transdermal approach for targeted breast cancer therapy, offering improved bioavailability, reduced side effects, and better patient compliance.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"1530-1545"},"PeriodicalIF":5.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946452","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":"Clinically translatable anti-fibrotic nanosuspension for inhaled treatment of idiopathic pulmonary fibrosis.","authors":"Daiheon Lee, Byoungjae Kong, Gijung Kwak, Bokyung Kang, Carter Swaby, Rachel Fanaroff, Venkataramana Sidhaye, Jung Soo Suk","doi":"10.1007/s13346-025-01973-y","DOIUrl":"10.1007/s13346-025-01973-y","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by chronic pulmonary fibrosis, irreversible lung function decline, and high mortality rate. Oral nintedanib (NTB) is one of the rare anti-fibrotic drugs clinically available for managing the condition but suffers from poor bioavailability and lung delivery efficiency as well as numerous off-target adverse effects. To address these critical limitations, we developed a nanosuspension (NS) formulation of NTB (NTB-NS) for inhaled treatment of IPF. The formulation is composed entirely of FDA-approved materials, including NTB and polysorbate 80, a surfactant approved for respiratory use in a clinic, and can be freeze-dried to a powder form for long-term storage and remote shipping without perturbing the physicochemical properties and drug activity. NTB-NS locally administered via oropharyngeal administration exhibited favorable pharmacokinetics over the standard oral administration of nintedanib esylate (NTB-esy), resulting in comprehensive anti-inflammatory and anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrosis. Notably, locally administered NTB-NS, but not oral NTB-esy, normalized several key lung function parameters in the model despite the use of 60-fold and 3-fold lower dose and dosing frequency, respectively. The findings here may open a new avenue for the treatment of IPF and potentially other fibrotic lung diseases in the clinic.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"1581-1591"},"PeriodicalIF":5.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148273","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":"Image-guided in vivo evaluation and comparison of bone-targeting peptides for therapeutic intervention.","authors":"Austin Stellpflug, Amit Joshi, Shue Wang, Linxia Gu, Rongxue Wu, Bo Wang","doi":"10.1007/s13346-025-01968-9","DOIUrl":"10.1007/s13346-025-01968-9","url":null,"abstract":"<p><p>Hydroxyapatite (HA)-binding peptides hold strong potential for bone-targeted therapies due to their high affinity for mineralized tissues. However, most existing studies have primarily focused on in vitro binding characterization, offering limited insight into their in vivo biodistribution and bone-binding performance. In this study, we evaluated the in vivo behavior of four HA-binding peptides, including D8, E8, YD8, and YE8, using fluorescence imaging to assess biodistribution in both healthy and pathological bone environments. In healthy animals, D8 showed the strongest bone-binding capacity, with prominent localization in the skull, femur, and tibia, while YD8 exhibited moderate binding. E8 and YE8 showed more limited localization, influenced by peptide dosage and binding kinetics. In pathological models, including tibial defects and osteogenesis imperfecta (OIM) mice, D8 and YD8 preferentially accumulated in compromised bone regions, highlighting their potential utility in targeting diseased bone microenvironments. Fluorescence imaging combined with spectral unmixing algorithms enabled effective visualization and quantification of peptide localization and distribution. These findings emphasize the value of in vivo studies for advancing the therapeutic and diagnostic applications of HA-binding peptides. The results provide a foundation for optimizing peptide design to improve specificity and efficacy in bone repair and regeneration.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"1547-1560"},"PeriodicalIF":5.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069376","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":"From simulation to application: enhancing preclinical evaluation of dissolvable microarray patches through PBPK modelling.","authors":"Maja Railic, Wilhelmus E A de Witte, Stephan Schaller, Sarah Toluwanimi Agboola, Ziad Sartawi, Waleed Faisal, Mohamed Elkhashab, Abina Crean, Sonja Vucen","doi":"10.1007/s13346-025-01974-x","DOIUrl":"10.1007/s13346-025-01974-x","url":null,"abstract":"<p><p>Dissolvable microarray patches (MAP) represent a promising drug delivery platform; however, the absence of standardised protocols for their preclinical evaluation poses a significant barrier to regulatory approval and clinical translation. Physiologically Based Pharmacokinetic (PBPK) modelling is a powerful tool for predicting drug kinetics following MAP application, addressing key challenges associated with in vitro and in vivo studies such as experimental variability, complex study design, and data extrapolating across different populations. However, adapting PBPK models for dissolvable MAP is inherently complex due to the interplay between microneedle geometry, drug release kinetics, and skin physiology. In this study, an existing dermal PBPK model in MoBi^® was optimised for dissolvable MAP by incorporating microneedle geometry and in vitro release profiles of MAP formulations containing the antihistamines loratadine (LOR) and chlorpheniramine maleate (CPM), as well as the antifungal drug itraconazole (ITZ). Model refinement involved systematically optimising input parameters related to skin thickness and drug-skin diffusion, partitioning and binding, to enhance predictive accuracy. Validation was performed using in vitro permeation testing with porcine skin for CPM and LOR MAP, alongside in vivo preclinical studies in pigs for ITZ MAP. The optimised model demonstrated robust predictive performance across the diverse drug molecules and experimental conditions investigated, highlighting its value as a powerful tool to accelerate preclinical MAP development.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"1592-1606"},"PeriodicalIF":5.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive review of thermal ablation technologies for transdermal drug delivery: mechanisms, commercial products, and future smart systems.","authors":"Muhammad Murtaza, Salman Ali Khan, Hayat Khan, S K Safdar Hossain","doi":"10.1007/s13346-026-02081-1","DOIUrl":"https://doi.org/10.1007/s13346-026-02081-1","url":null,"abstract":"<p><p>The skin is the body's largest organ and is considered as a protective barrier which acts as a highly impermeable region of the human body. But in recent times, it is recognized as a specialized organ that aids in the delivery of a wide range of drug molecules into the skin (intradermal drug delivery) and across the skin into systemic circulation (transdermal drug delivery, TDD). Transdermal administration remains an active research and development area as an alternative route for long- acting drug delivery. It avoids major drawbacks of conventional oral (gastrointestinal side effects, low drug bioavailability, and need for multiple dosing) or parenteral routes (invasiveness, pain, and psychological stress and bio-hazardous waste generated from needles), thereby increasing patient appeal and compliance. The bioavailability of a drug administered transdermally can be improved by several penetration enhancement techniques, which are broadly classified into chemical and physical techniques. Application of the mentioned techniques together with efforts of various scientific and innovative companies had made TDD a multibillion-dollar market and this has led to a growing market with a steady pipeline of new transdermal products receiving regulatory approval. Out of various techniques, thermal therapeutic methods including chemical heating, laser ablation, thermoporation, radiofrequency and photothermal therapy are the top listed emerging techniques. This review article mainly discussed about these thermal ablation techniques with their available commercial products along with advantages and disadvantages. This review also presented anatomy of the skin, penetration pathways across the skin, affecting factors and different generations and mechanisms of TDD. Briefly, this article discussed basics, mechanism, challenges, and future research and development directions of thermal-based TDDS.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812457","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":"Self-assembling RADA16-I peptide in situ hydrogel loaded with Celastrol boost immunogenic cell death in oral squamous cell carcinoma.","authors":"Chanjuan Zhang, Jiajun Wu, Hongfang Li, Yaning Shi, Yantian Liang, Jingxin Chen, Li Qin","doi":"10.1007/s13346-025-01938-1","DOIUrl":"10.1007/s13346-025-01938-1","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of the head and neck and is characterized by high heterogeneity and high recurrence rates. In particular, the serious side effects of radiotherapy and chemotherapy are the main obstacles in OSCC treatment. It is worth noting that immune infiltration is associated with the occurrence of OSCC. However, the effective induction of a robust immune response remains challenging because of the limited responsiveness of most patients with oral cancer. Celastrol (CeT) has excellent therapeutic efficacy against cancers, but is poorly soluble in water. We used RADA16-I hydrogel loaded with CeT (RADA-CeT) to improve its solubility and stability. The results indicated that the complex formed by the interaction between RADA16-I and CeT exhibited better stability, smaller particle size, excellent dispersibility, and high elasticity. Particularly, RADA-CeT hydrogel was more effective in activating damage-associated molecular patterns, thereby evoking immunogenic cell death (ICD) in OSCC cells. In vivo experiments demonstrated that RADA-CeT hydrogel had a stronger promoting effect on the expressions of CD4, CD8, calreticulin (CRT), and high-mobility group box-1 (HMGB1). Thus, RADA-CeT exhibited excellent anti-tumor efficacy by amplifying ICD. In the present study, we developed a biocompatible drug delivery system for uncaging the power of CeT in OSCC immunotherapy.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"1372-1387"},"PeriodicalIF":5.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871941","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":"Microneedle-mediated delivery of hydroxypropyl-β-cyclodextrin-encapsulated Angelica sinensis (Danggui) essential oil for acne treatment: efficacy and mechanisms.","authors":"Xiaoli Liu, Xiaojuan Li, Weijun He, Xiaoyu Han, Ting Xiao, Shiqi Guo, Yujie Jia, Liqun Lin, Ming Yang, Li Wang, Yuehong Xu","doi":"10.1007/s13346-025-01953-2","DOIUrl":"10.1007/s13346-025-01953-2","url":null,"abstract":"<p><p>Acne is a multifactorial dermatological condition driven by Propionibacterium acnes (P. acnes) infection, inflammation, and sebum dysregulation. While essential oils, such as Angelica sinensis (Danggui) essential oil (AEO), exhibit antimicrobial and anti-inflammatory properties, their clinical application is hindered by poor solubility, stability, and skin penetration. To address these limitations, we developed hydroxypropyl-β-cyclodextrin (HPCD)-complexed AEO-loaded microneedles (AEO@HPCD MNs) using hyaluronic acid for enhanced transdermal delivery. The optimized AEO@HPCD MNs demonstrated superior mechanical strength, rapid dissolution, and efficient cargo release. In vitro studies confirmed potent antibacterial activity against P. acnes, while in vivo experiments revealed significant reductions in acne lesion size and IL-1β levels. RNA sequencing of treated acne lesions identified key downregulated genes (Fpr1, Rarres2, Cxcl5, Gbp3, Hck, Gbp7, Librb4a, Psmb8) and enriched pathways, including innate immunity and inflammatory responses. Notably, AEO@HPCD MNs suppressed 5α-reductase and fatty acid synthase (FAS) expression, demonstrating-for the first time-AEO's ability to normalize sebum production. Mechanistically, AEO@HPCD MNs exert multifaceted therapeutic effects: (1) direct antibacterial activity against P. acnes, (2) suppression of inflammatory and immune-related pathways through modulation of Toll-like receptor, NOD-like receptor, and cytokine-cytokine receptor signaling pathways, (3) regulation of sebum production via lipid-metabolic gene expression modulation, and (4) enhanced delivery efficiency and microenvironment modification through the physical action of microneedles, collectively contributing to synergistic acne therapy. This study develops a microneedle delivery platform that addresses both essential oil instability and inclusion complex delivery challenges while targeting multiple acne pathogenic factors. The AEO@HPCD MNs provide a safe, minimally invasive, multifunctional therapeutic strategy for acne treatment.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"1461-1478"},"PeriodicalIF":5.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946854","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":"Mesoporous silica nanoparticles with an azobenzene gatekeeper as hypoxia-responsive nanocarriers for targeted doxorubicin delivery.","authors":"Paula Rodrigo-Martínez, Mariana Barros, María Carmen Terencio, Eva Garrido, Pau Arroyo, Jose A Sáez, Margarita Parra, Pablo Gaviña","doi":"10.1007/s13346-025-01950-5","DOIUrl":"10.1007/s13346-025-01950-5","url":null,"abstract":"<p><p>Hypoxia is a key feature of solid tumors, contributing to therapeutic resistance and poor prognosis. Targeting hypoxic environments presents an opportunity to enhance drug delivery selectivity and improve treatment outcomes. Among nanocarriers, mesoporous silica nanoparticles (MSNs) have demonstrated great potential for drug delivery; however, achieving precise control over drug release remains a challenge. In this work, we develop an enzyme-responsive MSN system for targeted drug delivery in hypoxic tumors. MSNs were loaded with the chemotherapeutic drug doxorubicin (Dox) and capped with an azobenzene (Azo) gatekeeper. The bulky Azo group acts as a responsive molecular gate that remains closed under normoxic conditions but undergoes enzymatic cleavage by azoreductases, which are overexpressed in hypoxic tumor microenvironment. This cleavage triggers the uncapping of the pores, inducing the release of Dox specifically in the hypoxic region, minimizing premature drug leakage and off-target toxicity. In vitro studies with A549 cells (which overexpress azoreductase) and THP-1 cells (with low expression of azoreductases) under normoxic and hypoxic conditions, demonstrated a significant increase in Dox release and cytotoxicity in the A549 cells compared with the THP-1, which was more pronounced under hypoxia. These findings highlight the potential of enzyme-responsive MSNs as a promising strategy for selective drug delivery in hypoxic tumors.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"1423-1434"},"PeriodicalIF":5.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13038766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}