*4.7. Ginger-Synthesised Iron Nanoparticles*

Nanotechnology, the understanding and control of matter generally in the 1–100 nm dimension, is gaining much medical research as it holds the potential for breakthroughs in preventing, diagnosing, and treating various diseases due to the unique physicochemical properties of nanomaterials [163,164]. Unsurprisingly, iron nanoparticle (FeNP) preparations have also been developed to overcome the inherent limitations of conventional ferrous and ferric iron formulations in the treatment of IDA. Pre-clinical studies showed that iron nanoparticles have high bioavailability, are non-toxic, and induce lesser side effects than conventional iron preparations for IDA, even though the delivery and safety issues in humans for therapeutic use required further research [165]. The high bioavailability of iron nanoparticles is also ideal for food fortifications as the nanoparticles do not cause unacceptable taste or colour in food vehicles. Hence, it is suggested that nanosized iron salts can have potential applications in food fortification to reduce IDA worldwide [166].

Ginger has been used in the green approach for metallic nanoparticles, including iron. The green synthesis approach is preferred to avoid the production of unwanted or harmful chemical by-products and achieve a cost-effective and sustainable supply of nanoparticles [167]. El-Refai et al. [155] used ginger and garlic extracts to synthesise silver, copper, iron, and zinc nanoparticles, and their antioxidant and antimicrobial activities were evaluated. The high flavonoid and phenolic contents in garlic and ginger water extracts revealed in the phytochemical analysis strongly support the potential of garlic and ginger to bio-reduce the metallic ions to their respective nanoparticles (e.g., Fe3+ ions to FeNPs). Transmission electron microscopy showed that the FeNPs in ginger were in the range of 14.08–21.57 nm with almost spherical forms. In comparison, the particle size of FeNPs in garlic ranged from 60.30 to 82.63 nm with tetragonal structures. All nanoparticles extracted in this study, including FeNPs from ginger, demonstrated considerable radical scavenging properties and antimicrobial activities against Gram-positive and Gram-negative bacteria and fungi [155]. Other researchers have similarly shown ginger to be a suitable green material for synthesising FeNPs with high antioxidant and antibacterial properties [156,157].

#### **5. Conclusions**

In summary, ginger with its rich polyphenols can support IDA treatment and prevention in many ways. It can improve iron bioavailability by enhancing iron absorption and thus increasing the efficacy of oral iron therapy. Its antioxidant and anti-inflammatory properties help in reducing oxidative stress and pro-inflammatory cytokine cascade and thus protect the gastrointestinal tract from the delirious effects of excess free iron. Ginger and its bioactive polyphenols can also serve as prebiotics to the gut microbiota to promote gut health and potentially reduce the unwanted side effects of oral iron therapy. Ginger can also stimulate erythropoiesis to generate the much-needed healthy RBCs for proper functioning. In the case of iron overload due to comorbidities from inflammatory disorders or chronic conditions, ginger can potentially reverse the adverse impacts and restore iron balance. Ginger can also be used to synthesise FeNPs sustainably to develop newer and more effective oral iron products and functional ingredients for IDA treatment and prevention.

There are, however, still many unknowns regarding the physiological effects of ginger and its active compounds in IDA. Much research is still needed to understand how the phenolic compounds of ginger can influence the mechanistic pathways of iron absorption and metabolism. More pre-clinical studies are required to further explore how ginger's antioxidant, anti-inflammatory, gut microbiota modulation, and erythropoiesis stimulation properties can affect IDA in areas such as side effects induced by oral iron therapy, gastrointestinal micro-environment and microbiota changes, inflammatory cytokine signalling and erythropoiesis effectiveness. Most importantly, there is a lack of clinical study on the effect of co-administration of ginger and oral iron therapy for IDA treatment other than one short human trial. There is a need for a longer-term, randomised, double-blind placebo-controlled trial to validate the effectiveness of ginger as an adjuvant treatment for IDA.

To conclude, polyphenol-rich ginger can play a much bigger role in addressing the global public health problem of IDA, but more research and development are needed to realise its full potential.

**Author Contributions:** Conceptualization, S.L.O. and S.C.P.; writing—original draft preparation, S.L.O.; writing—review and editing, S.C.P., R.C. and A.M.; visualization, S.L.O.; supervision, S.C.P.; project administration, S.C.P.; funding acquisition, S.L.O., S.C.P. and R.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Australian Traditional-Medicine Society (ATMS) through the ATMS Research Grant 2021.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**

The following abbreviations are used in this manuscript:


