Abstract
Polyphenols, abundant compounds found in natural sources, exhibit various biological activities, including immunomodulatory properties that can either stimulate or suppress immune responses, making them promising for therapeutic applications. However, their poor solubility, low bioavailability, rapid metabolism, and non-specific distribution require advanced drug delivery strategies to overcome limitations in clinical translations. Therefore, nano-drug delivery systems have been intensively studied to explore the full therapeutic potential of polyphenols. Distinct from conventional paradigms where polyphenols serve solely as active compounds, this review advances the concept of polyphenol-based nanomedicine as dual-functional platforms: bioactive structural components and intrinsic immune modulators. Recent strategies to improve the loading efficacy of polyphenols, enhance their cellular uptake, prolong circulation, and enhance specific delivery based on those nanocarriers are emphasized. In addition, polyphenol-based nanoparticles, in which polyphenols serve as structural components, were also studied as self-therapeutics or multifunctional nanocarriers for drug delivery. We intensively focus on their immunomodulatory applications and highlight their potential in preclinical as well as clinical settings for the treatment of various diseases and therapeutic purposes, including autoimmune diseases, cancer immunotherapy, vaccination, inflammation, and infectious diseases. Although polyphenol nanoparticle development has made significant advances, there remain challenges in formulation stability, unclear in vivo toxicity profiles, and clinical translation. Further studies on optimizing nanoparticle design and assessing long-term toxicity are necessary to materialize their application. A combination of polyphenol nanoparticles with other immunotherapies may promise a pronounced efficacy and safety profile.