Advances in Nrf2 Signaling Pathway by Targeted Nanostructured-Based Drug Delivery Systems

Abstract

Nanotechnology has gained significant interest in various applications, including sensors and therapeutic agents for targeted disease sites. Several pathological consequences, including cancer, Alzheimer's disease, autoimmune diseases, and many others, are mostly driven by inflammation and Nrf2, and its negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), plays a crucial role in maintaining redox status, the expression of antioxidant genes, and the inflammatory response. Interestingly, tuning the Nrf2/antioxidant response element (ARE) system can affect immune-metabolic mechanisms. Although many phytochemicals and synthetic drugs exhibited potential therapeutic activities, poor aqueous solubility, low bioavailability, poor tissue penetration, and, consequently, poor specific drug targeting, limit their practical use in clinical applications. Also, the therapeutic use of Nrf2 modulators is hampered in clinical applications by the absence of efficient formulation techniques. Therefore, we should explore the engineering of nanotechnology to modulate the inflammatory response via the Nrf2 signaling pathway. This review will initially examine the role of the Nrf2 signaling pathway in inflammation and oxidative stress-related pathologies. Subsequently, we will also review how custom-designed nanoscale materials encapsulating the Nrf2 activators can interact with biological systems and how this interaction can impact the Nrf2 signaling pathway and its potential outcomes, emphasizing inflammation.

Keywords: Nrf2 signaling pathway; drug delivery; drug targeting agents; nanotechnology; oxidative stress.

Figure 1

Nrf2 signaling pathway. Keap1 homo-dimerizes via the N-terminal BTB domain under normal homeostatic conditions, and it binds to the (Cul3) E3 ligase to form the Keap1-Cul3-RBX1-E3 ligase complex, which causes Nrf2 ubiquitination. Stress causes Nrf2 to be released from the Keap1-Cul3-RBX1 complex and move into the nucleus, where it binds to the antioxidant response elements (AREs) and hetero-dimerizes with sMaf proteins to cause the transcription of ARE-driven genes.

Figure 2

Cross-link of Nrf2 and NF-κB in inflammation. The IKK complex phosphorylates NF-κB, freeing it from IκB in response to TLR signaling. Following its translocation into the nucleus, NF-κB stimulates the production of proinflammatory mediators. Nanostructures stimulate Nrf2, which prevents IκB-α degradation and oxidative stress-mediated NF-κB activation and nuclear translocation.

Figure 3

The passive drug targeting in tissue penetration from nanostructures. The design and synthesis of nanostructures are composed in such a way that their retention time in the body increases, correlated with particle size.