{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:02:10Z","timestamp":1787029330521,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Innovation Method Special Project","award":["2020IM010500"],"award-info":[{"award-number":["2020IM010500"]}]},{"name":"University-level Innovation Team for the Development and Evaluation of High-quality Traditional Chinese Medicine Health Products","award":["CXTD-22004"],"award-info":[{"award-number":["CXTD-22004"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Ulcerative colitis (UC) involves chronic colon inflammation and oxidative stress. Treating UC is challenging due to systemic drug side effects and poor targeted delivery. Nanocarriers responsive to the UC microenvironment, particularly elevated reactive oxygen species (ROS), could overcome these limitations. This study developed an oral delivery system for ROS-triggered drug release and active targeting. Using ferulic acid (FER), a system was designed to enhance site-specific accumulation and therapeutic efficacy against colitis. Methods: A ROS-sensitive covalent organic framework (COF) was synthesized from \u03b3-cyclodextrin and functionalized with folic acid (FA) to create a carrier (COF-FA) designed for potential active targeting. This carrier was loaded with FER to form FER@COF-FA. The system was characterized (SEM, FTIR, TGA), and its ROS scavenging and sustained drug release profiles were confirmed in vitro. Biocompatibility was evaluated in cell lines, and therapeutic efficacy was tested in a DSS-induced murine colitis model. Results: The synthesized FER@COF-FA demonstrated high drug loading, potent ROS-scavenging capability, and a sustained drug release profile. It showed excellent biocompatibility and, in the murine model, significantly outperformed free FER. Treatment alleviated disease severity, prevented colon shortening, restored healthy tissue histology, and rebalanced pro- and anti-inflammatory cytokines. Conclusions: The FER@COF-FA system represents a highly promising therapeutic strategy for UC. Its superior efficacy is attributed to a synergistic multi-mechanism approach, combining sustained release, ROS-responsive drug delivery, intrinsic antioxidant activity, and potential folate receptor-mediated targeting, which collectively enhance site-specific accumulation and therapeutic outcomes in the inflammatory colon microenvironment.<\/jats:p>","DOI":"10.3390\/pharmaceutics17101263","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T12:33:03Z","timestamp":1758889983000},"page":"1263","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Folate-Functionalized ROS-Scavenging Covalent Organic Framework for Oral Targeted Delivery of Ferulic Acid in Ulcerative Colitis"],"prefix":"10.3390","volume":"17","author":[{"given":"Jin","family":"Xue","sequence":"first","affiliation":[{"name":"Formula-Pattern Research Center, Jiangxi University of Chinese Medicine, No. 1688, Meiling Road, Nanchang 330004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zifan","family":"Qiao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Chinese Medicine, No. 1688, Meiling Road, Nanchang 330004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang 330013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6518-0749","authenticated-orcid":false,"given":"Mubarak G.","family":"Bello","sequence":"additional","affiliation":[{"name":"Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Chinese Medicine, No. 1688, Meiling Road, Nanchang 330004, China"},{"name":"Department of Pharmaceutics and Industrial Pharmacy, Kaduna State University, Kaduna PMB 2339, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6313-6496","authenticated-orcid":false,"given":"Lihua","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Chinese Medicine, No. 1688, Meiling Road, Nanchang 330004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1515\/jbcpp-2018-0036","article-title":"Immune Response and Inflammatory Pathway of Ulcerative Colitis","volume":"30","author":"Chatuphonprasert","year":"2018","journal-title":"J. Basic Clin. Physiol. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Saez, A., Herrero-Fernandez, B., Gomez-Bris, R., S\u00e1nchez-Martinez, H., and Gonzalez-Granado, J.M. (2023). Pathophysiology of Inflammatory Bowel Disease: Innate Immune System. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021526"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s12950-020-00246-4","article-title":"Ulcerative Colitis: Understanding Its Cellular Pathology Could Provide Insights into Novel Therapies","volume":"17","author":"Kaur","year":"2020","journal-title":"J. Inflamm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4965","DOI":"10.1007\/s10787-025-01906-8","article-title":"Ajazuddin Recent Advances in the Therapeutics and Modes of Action of a Range of Agents Used to Treat Ulcerative Colitis and Related Inflammatory Conditions","volume":"33","author":"Patel","year":"2025","journal-title":"Inflammopharmacol"},{"key":"ref_5","first-page":"3204","article-title":"Current Treatment of Ulcerative Colitis","volume":"17","author":"Meier","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1046\/j.1365-2036.1999.00511.x","article-title":"Immunosuppressive Therapy for Ulcerative Colitis: Results of a Nation-wide Survey among Consultant Physician Members of the British Society of Gastroenterology","volume":"13","author":"Stack","year":"2001","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/17474124.2025.2457451","article-title":"Comprehensive Care of Ulcerative Colitis: New Treatment Strategies","volume":"2","author":"Chaemsupaphan","year":"2025","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1093\/ibd\/izab277","article-title":"Excessive Apoptosis in Ulcerative Colitis: Crosstalk Between Apoptosis, ROS, ER Stress, and Intestinal Homeostasis","volume":"28","author":"Wan","year":"2022","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1038\/s41467-023-39173-2","article-title":"Selective Oxidative Protection Leads to Tissue Topological Changes Orchestrated by Macrophage during Ulcerative Colitis","volume":"14","author":"Du","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1016\/j.ymthe.2023.02.017","article-title":"Reactive Oxygen Species-Responsive Nanocarrier Ameliorates Murine Colitis by Intervening Colonic Innate and Adaptive Immune Responses","volume":"31","author":"Yan","year":"2023","journal-title":"Mol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.2217\/nnm.14.237","article-title":"Comparison of Nanoparticle Penetration into Solid Tumors and Sites of Inflammation: Studies Using Targeted and Nontargeted Liposomes","volume":"10","author":"Poh","year":"2015","journal-title":"Nanomedicine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1080\/10717544.2021.1909175","article-title":"Role of Macrophage in Nanomedicine-Based Disease Treatment","volume":"28","author":"Song","year":"2021","journal-title":"Drug Deliv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1093\/ecco-jcc\/jjz113","article-title":"Oral Targeted Delivery by Nanoparticles Enhances Efficacy of an Hsp90 Inhibitor by Reducing Systemic Exposure in Murine Models of Colitis and Colitis-Associated Cancer","volume":"14","author":"Yang","year":"2020","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Cai, Y., Zhang, L., Zhang, Y., and Lu, R. (2022). Plant-Derived Exosomes as a Drug-Delivery Approach for the Treatment of Inflammatory Bowel Disease and Colitis-Associated Cancer. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14040822"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2544689","DOI":"10.1080\/10717544.2025.2544689","article-title":"Advances in Oral Treatment of Inflammatory Bowel Disease Using Protein-Based Nanoparticle Drug Delivery Systems","volume":"32","author":"Lin","year":"2025","journal-title":"Drug Deliv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1600124","DOI":"10.1002\/advs.201600124","article-title":"Reactive-Oxygen-Species-Responsive Drug Delivery Systems: Promises and Challenges","volume":"4","author":"Saravanakumar","year":"2017","journal-title":"Adv. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16790","DOI":"10.1007\/s10853-021-06338-7","article-title":"Interplay of Reactive Oxygen Species (ROS) and Tissue Engineering: A Review on Clinical Aspects of ROS-Responsive Biomaterials","volume":"56","author":"Tyagi","year":"2021","journal-title":"J. Mater. Sci."},{"key":"ref_18","first-page":"101","article-title":"ROS-Responsive Drug Delivery Systems for Biomedical Applications","volume":"13","author":"Tao","year":"2018","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.jsps.2014.10.001","article-title":"Microparticles as Controlled Drug Delivery Carrier for the Treatment of Ulcerative Colitis: A Brief Review","volume":"24","author":"Nidhi","year":"2016","journal-title":"Saudi Pharm. J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gvozdeva, Y., and Staynova, R. (2025). pH-Dependent Drug Delivery Systems for Ulcerative Colitis Treatment. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17020226"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2219427","DOI":"10.1080\/10717544.2023.2219427","article-title":"Responsive Nanosystems for Targeted Therapy of Ulcerative Colitis: Current Practices and Future Perspectives","volume":"30","author":"Chen","year":"2023","journal-title":"Drug Deliv."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.colsurfb.2015.07.081","article-title":"Oral Administration of pH-Sensitive Curcumin-Loaded Microparticles for Ulcerative Colitis Therapy","volume":"135","author":"Xiao","year":"2015","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ekhtiar, M., Ghasemi-Dehnoo, M., Azadegan-Dehkordi, F., and Bagheri, N. (2025). Evaluation of Anti-Inflammatory and Antioxidant Effects of Ferulic Acid and Quinic Acid on Acetic Acid-Induced Ulcerative Colitis in Rats. J. Biochem. Mol. Toxicol., 39.","DOI":"10.1002\/jbt.70169"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Liu, J., Guan, Y., Yang, L., Fang, H., Sun, H., Sun, Y., Yan, G., Kong, L., and Wang, X. (2025). Ferulic Acid as an Anti-Inflammatory Agent: Insights into Molecular Mechanisms, Pharmacokinetics and Applications. Pharmaceuticals, 18.","DOI":"10.3390\/ph18060912"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7328","DOI":"10.1039\/D2TB00874B","article-title":"Chitosan-Based Oral Colon-Specific Delivery Systems for Polyphenols: Recent Advances and Emerging Trends","volume":"10","author":"Chen","year":"2022","journal-title":"J. Mater. Chem. B"},{"key":"ref_26","first-page":"100063","article-title":"A Critical Appraisal on Ferulic Acid: Biological Profile, Biopharmaceutical Challenges and Nano Formulations","volume":"5","author":"Raj","year":"2022","journal-title":"Health Sci. Rev."},{"key":"ref_27","first-page":"e68063","article-title":"Ferulic Acid: A Comprehensive Review","volume":"16","author":"Purushothaman","year":"2024","journal-title":"Cureus"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"38421","DOI":"10.1021\/acsami.2c05220","article-title":"Antioxidant Biodegradable Covalent Cyclodextrin Frameworks as Particulate Carriers for Inhalation Therapy against Acute Lung Injury","volume":"14","author":"He","year":"2022","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"150345","DOI":"10.1016\/j.cej.2024.150345","article-title":"Polyrotaxanated Covalent Organic Frameworks Based on \u03b2-Cyclodextrin towards High-Efficiency Synergistic Inactivation of Bacterial Pathogens","volume":"486","author":"Yue","year":"2024","journal-title":"Chem. Eng. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"123684","DOI":"10.1016\/j.carbpol.2025.123684","article-title":"Cyclodextrin Metal-Organic Framework Design Principles and Functionalization for Biomedical Application","volume":"364","author":"Bello","year":"2025","journal-title":"Carbohydr. Polym."},{"key":"ref_31","first-page":"100833","article-title":"Luteolin Stabilized in Nanosheet and Cubic \u03b3-Cyclodextrin-Based Metal Organic Framework for Enhanced Bioavailability and Anti-Inflammatory Therapy","volume":"10","author":"Bello","year":"2025","journal-title":"Carbohydr. Polym. Technol. Appl."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"155700","DOI":"10.1016\/j.cej.2024.155700","article-title":"Targeted Quercetin Delivery Nanoplatform via Folic Acid-Functionalized Metal-Organic Framework for Alleviating Ethanol-Induced Gastric Ulcer","volume":"498","author":"Zhao","year":"2024","journal-title":"Chem. Eng. J."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wu, W., Liang, Y., Zhao, R., Shi, Y., Hou, J., Peng, J., Pan, J., Li, X., and Zhou, J. (2025). Establishment and Validation of HPLC Methods for the Determination of Folic Acid and Parabens Antimicrobial Agents on Folic Acid Oral Solution. BMC Chem., 19.","DOI":"10.1186\/s13065-024-01370-5"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3671","DOI":"10.1021\/acs.biomac.4c00261","article-title":"Ambient Synthesis of Porphyrin-Based Fe-Covalent Organic Frameworks for Efficient Infected Skin Wound Healing","volume":"25","author":"Chen","year":"2024","journal-title":"Biomacromolecules"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12073","DOI":"10.1021\/acsomega.0c00277","article-title":"Improvement of the Solubility and Evaluation of the Physical Properties of an Inclusion Complex Formed by a New Ferulic Acid Derivative and \u03b3-Cyclodextrin","volume":"5","author":"Ikeda","year":"2020","journal-title":"ACS Omega"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1007\/s00535-022-01862-y","article-title":"A Review on the Current Status and Definitions of Activity Indices in Inflammatory Bowel Disease: How to Use Indices for Precise Evaluation","volume":"57","author":"Kishi","year":"2022","journal-title":"J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2000147","DOI":"10.1002\/ppsc.202000147","article-title":"Facile Synthesis and Size Control of 2D Cyclodextrin-Based Metal\u2013Organic Frameworks Nanosheet for Topical Drug Delivery","volume":"37","author":"Bello","year":"2020","journal-title":"Part. Part. Syst. Charact."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.1021\/acs.cgd.9b00319","article-title":"CD-MOFs Crystal Transformation from Dense to Highly Porous Form for Efficient Drug Loading","volume":"19","author":"Ding","year":"2019","journal-title":"Cryst. Growth Des."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2411979","DOI":"10.1002\/adfm.202411979","article-title":"Reactive Oxygen Species Triggered Cleavage of Thioketal-Containing Supramolecular Nanoparticles for Inflammation-Targeted Oral Therapy in Ulcerative Colitis","volume":"35","author":"Xiong","year":"2025","journal-title":"Adv. Funct. Mater."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.saa.2015.03.078","article-title":"Fabrication and Spectroscopic Studies of Folic Acid-Conjugated Fe3O4@Au Core\u2013Shell for Targeted Drug Delivery Application","volume":"148","author":"Karamipour","year":"2015","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1007\/s00289-011-0674-x","article-title":"Preparation, Characterization, and in Vitro Release of Folic Acid-Conjugated Chitosan Nanoparticles Loaded with Methotrexate for Targeted Delivery","volume":"68","author":"Ji","year":"2012","journal-title":"Polym. Bull."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5175","DOI":"10.1039\/D1CS00550B","article-title":"Cyclodextrin Metal\u2013Organic Frameworks and Derivatives: Recent Developments and Applications","volume":"51","author":"Dummert","year":"2022","journal-title":"Chem. Soc. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1007\/s10973-016-5654-9","article-title":"Compatibility Study between Ferulic Acid and Excipients Used in Cosmetic Formulations by TG\/DTG, DSC and FTIR","volume":"127","author":"Bezerra","year":"2017","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1002\/fft2.366","article-title":"The Intestinal Delivery Systems of Ferulic Acid: Absorption, Metabolism, Influencing Factors, and Potential Applications","volume":"5","author":"Chen","year":"2024","journal-title":"Food Front."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3082","DOI":"10.1021\/acs.biomac.7b00728","article-title":"Folate-Targeted Dendrimers Selectively Accumulate at Sites of Inflammation in Mouse Models of Ulcerative Colitis and Atherosclerosis","volume":"18","author":"Poh","year":"2017","journal-title":"Biomacromolecules"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.nano.2018.01.009","article-title":"Selective Liposome Targeting of Folate Receptor Positive Immune Cells in Inflammatory Diseases","volume":"14","author":"Poh","year":"2018","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"155415","DOI":"10.1016\/j.phymed.2024.155415","article-title":"Effects of Folate-Chicory Acid Liposome on Macrophage Polarization and TLR4\/NF-\u03baB Signaling Pathway in Ulcerative Colitis Mouse","volume":"128","author":"Yang","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s11307-015-0876-y","article-title":"Predicting Response to Therapy for Autoimmune and Inflammatory Diseases Using a Folate Receptor-Targeted Near-Infrared Fluorescent Imaging Agent","volume":"18","author":"Kelderhouse","year":"2016","journal-title":"Mol. Imaging Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/0471142735.im1525s104","article-title":"Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice","volume":"104","author":"Chassaing","year":"2014","journal-title":"CP Immunol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/10\/1263\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T16:47:36Z","timestamp":1759250856000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/10\/1263"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,26]]},"references-count":49,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["pharmaceutics17101263"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17101263","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,26]]}}}