FLAVONOID-BASED NANOTHERAPEUTICS: RECENT ADVANCES IN DELIVERY SYSTEMS, PHARMACOKINETICS, THERAPEUTIC APPLICATIONS, AND CLINICAL TRANSLATION

Abstract

Flavonoids are a group of structurally diverse bioactive compounds with high therapeutic potential for diverse pathological conditions; however, their clinical translation is often limited by poor aqueous solubility, chemical instability, extensive metabolism, rapid elimination, and low systemic bioavailability. As such, nanotechnology has emerged as a promising approach to overcome these physicochemical and pharmacokinetic limitations by enabling controlled drug loading and release, improved solubility and stability, enhanced absorption, prolonged circulation, and targeted or tissue-specific delivery. This review critically surveys recent progress in flavonoid nanotherapeutics, covering lipid-based, polymeric, vesicular, biomimetic, inorganic and hybrid nanocarrier systems with an emphasis on formulation-property-performance relationships. The available evidence is evaluated in terms of physicochemical characterization, in vitro biological activity, animal pharmacokinetics and efficacy, human pharmacokinetic studies, and clinical investigations to distinguish between formulation feasibility and meaningful therapeutic benefit. In particular, the discussion focuses on changes of important pharmacokinetic parameters like systemic exposure, maximum plasma concentration, half-life, and bioavailability, realizing that better pharmacokinetic performance does not necessarily mean better clinical efficacy. The review also discusses nano-bio interactions, biodistribution, immunological and organ-specific safety, manufacturing and scale-up challenges, critical quality attributes and regulatory considerations that currently prevent clinical translation. Future progress relies on standardized characterization, reproducible manufacturing, robust long-term safety assessment, human-relevant pharmacokinetic and efficacy studies, and well-designed clinical trials. The translation of flavonoid nanotherapeutics from promising experimental systems into clinically viable therapeutic products may be enabled by the integration of formulation science and pharmacology, artificial intelligence, quality by design (QbD) principles, and regulatory science.