Flavonoid nanoformulations for cutaneous administration: overcoming delivery barriers for targeted therapeutics and bioavailability enhancement.

Flavonoids represent one of the most pharmacologically diverse classes of natural polyphenols, demonstrating broad therapeutic potential in oncology, neurodegeneration, cardiovascular, and metabolic disorders. However, their clinical utility has been limited by intrinsic physicochemical deficiencies, including low aqueous solubility, chemical instability, and extensive first-pass metabolism. Traditional formulation strategies have proven inadequate at overcoming these barriers. Nano-enabled delivery platforms circumvent these limitations through rational nanocarrier design, effectively enhancing dissolution kinetics, protecting labile compounds from degradation, and modulating tissue distribution. This comprehensive review critically examines the current landscape of flavonoid-loaded nanoformulations on the recent advancements (2020-2025), with a particular emphasis on cutaneous delivery (topical/transdermal), elucidating formulation-driven mechanisms of bioavailability enhancement. Furthermore, it critically highlights the growing significance of co-delivery approaches of flavonoids with other therapeutic agents or with each other within advanced nanoplatforms in improving therapeutic benefits or diminishing the drug's adverse effects. Nano-engineered delivery platforms effectively neutralize the bioavailability constraints of flavonoids, unlocking their full pharmacological potential and elevating clinical therapeutic efficacy.