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

Abstract

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.

Fig. 1. NRF2/KEAP1 signaling pathway in the basal state and under oxidative stress.

Fig. 2. Illustration and description of nano-drug delivery systems developed for the use of NRF2 modulators in various medical treatments.

Fig. 3. Distribution of approved particle-based formulations over the years (1989–2020). Reprinted with permission from ref. . Copyright 2021 Elsevier.

Fig. 4. Challenges encountered in the transition of nano drug carriers from research level to patient use.

Fig. 5. Nanotoxicological classification system (NCS) placing the particles according to size and persistency into four classes of increasing risk: I – no or low, II and III – medium, and IV – high risk. Reprinted with permission from ref. . Copyright 2021 Elsevier.