Purpose <p>The present review discusses the therapeutic potential of a flavonoid-naringenin (4,5,7-trihydroxyflavanone), found abundantly in citrus fruits, with an emphasis on its pharmacological benefits in disease management- cancer, neurodegenerative diseases, diabetes, cardiovascular issues, and inflammation. It further investigates state-of-the-art biomaterial-based nano delivery systems, including polymeric nanoparticles, in order to offset naringenin’s shortcomings in solubility and bioavailability, and increase its translational potential.</p> Methods <p>In this review, we have reviewed and discussed preclinical, clinical, and epidemiological study on naringenin pharmacological mechanisms, which targeted major signaling pathways such as PI3K/Akt, NF-κB, AMPK, and Nrf2. Furthermore, we reviewed the recent developments of nanodelivery systems (nanoemulsions, liposomes, polymeric nanoparticles, chitosan-based carriers) for amelioration of naringenin’s pharmacokinetic profile. The extraction, purification and characterization approaches evaluated for an overall view of its therapeutic exploitation.</p> Results <p>Naringenin has multiple therapeutic effects in various diseases, through acting on important signaling pathways and decreasing oxidative stress and inflammation; and by showing activity against cancer. Unfortunately, its clinical application limited due to its low water solubility, low bioavailability (15%), as well as rapid metabolism. Newly developed nanodelivery systems, especially polymeric nanoparticles, have greatly improved naringenin’s solubility (up to 314-fold with cyclodextrin complexes) and bioavailability (6-fold with PLA/PVA formulations), which promote the systemic delivery and therapeutic efficacy of NAR. These advances also have the potential for homing in on particular tissues (tumors, for example) and overcoming barriers (like the blood–brain barrier, which has been a formidable obstacle in treatments for neurodegenerative diseases).</p> Conclusion <p>By virtue of its extensive pharmacological actions, naringenin demonstrates great potential as a multifunctional therapeutic agent. The application of nanotechnology, in particular polymeric nanoformualtions, can circumnavigate its pharmacokinetic hurdles facilitating a successful clinical translation. More research, including strong clinical studies and investigation of directed delivery systems, required to better exploit the naringenin potential in treating complex diseases, such as cancer and neurodegenerative diseases.</p> Lay Summary <p>Naringenin, a natural agent derived from some citrus fruits including grapefruit and oranges, used for preventing list of serious health conditions including cancer, Alzheimer’s, diabetes, and, belly fat. It does so by affecting multiple processes in the body that influence inflammation, cell growth, and damage from harmful molecules. But naringenin is not soluble in water and metabolized quickly in the body, both of which reduce its efficacy. Tiny carriers, known as nanoparticles, have engineered by scientists to aid in more efficiently getting naringenin to the right places in the body where it can make a difference, namely tumors or the brain. The review also flags how emerging delivery methods could help turn naringenin into a mighty agent for good health, though more research needed before it crops up in everyday medical use.</p> Graphical Abstract <p></p>