Delivery strategies to improve the pharmacological efficacy of NRF2 modulators : a review

Sezgin-Bayindir, Zerrin (author), Sova, Matej (author), Nilüfer, Yüksel (author), Saso, Luciano (author)

The NRF2/KEAP1 signaling pathway regulates the gene expression of numerous cytoprotective and detoxifying enzymes and is therefore essential for maintaining cellular redox homeostasis. Despite the increasing knowledge of NRF2 signaling complexity, dimethyl fumarate remains the sole NRF2-targeting therapy in clinical practice, used for multiple sclerosis. Ongoing research exploring the role of NRF2 in cancer, neurodegeneration, diabetes, and cardiovascular, renal, and liver diseases holds significant promise for future therapeutic innovation. The therapeutic potential of NRF2 modulators, while supported by positive research and clinical data, is often restricted due to factors including low solubility, poor stability, poor pharmacokinetic parameters, and a lack of specificity that results in off-target effects. Therefore, designing an effective pharmaceutical formulation is one of the significant barriers to their clinical translation. This article addresses these challenges by reviewing various drug delivery strategies with a particular emphasis on polymeric nanoparticles, liposomes, polymeric micelles, carbon nanotubes, micro/nano-emulsions, and biomimetic nanoparticles. The potential of these systems to enhance the pharmacological activities of NRF2 modulators—driven by their small particle size and customizable properties—is discussed on a disease-by-disease basis, focusing on cancer, neurodegenerative, and inflammatory diseases. While these systems have shown considerable success in preclinical studies, their clinical application is constrained by hurdles in safety, scalability, stability and regulatory compliance. This transition has not yet been achieved for NRF2 modulators, but intensive research is ongoing. Therefore, the overall aim of this article is to provide a comprehensive understanding of delivery strategies for NRF2 modulators, ultimately guiding the development of more effective therapies and improving their clinical applications.

• Language: English
• Keywords: Nrf2 modulators, nanomedicine, nanomedicine-Nrf2 modulator synergy, the therapeutic potential of NRF2 modulators, chemopreventive agents, cancer therapeutics, neurological therapeutics, oxidative stress, signaling pathway
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 4599-4616
• Numbering: Vol. 16, iss. 10
• PID: 20.500.12556/RUL-175590
• UDC: 615.4:54:575.117
• ISSN on article: 2632-8682
• DOI: 10.1039/D5MD00571J
• COBISS.SI-ID: 254941443
• Publication date in RUL: 05.11.2025

Record is a part of a journal

• Title: RSC medicinal chemistry
• Shortened title: RSC med. chem.
• Publisher: Royal Society of Chemistry
• ISSN: 2632-8682
• COBISS.SI-ID: 304960512

Licences

• License: CC BY 3.0, Creative Commons Attribution 3.0 Unported
• Link: https://creativecommons.org/licenses/by/3.0/deed.en
• Description: You are free to reproduce and redistribute the material in any medium or format. You are free to remix, transform, and build upon the material for any purpose, even commercially. You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.

Secondary language

• Language: Slovenian
• Keywords: modulatorji Nrf2, nanomedicina, sinergija med nanomedicino in modulatorjem Nrf2, terapevtski potencial modulatorjev NRF2, kemopreventivna sredstva, zdravila za zdravljenje raka, nevrološka zdravila, oksidativni stres, signalna pot