Poly (Lactic-co-glycolic Acid)-Based Nanoparticles for Co-delivery and Targeted Delivery of Polyphenols in Cancer Therapy.

INTRODUCTION: Cancer remains a leading cause of mortality worldwide, and current conventional therapies are often limited by systemic toxicity, drug resistance, and tumour recurrence. Although natural polyphenols, such as Curcumin (CUR), Quercetin (QUE), Caffeic Acid Phenethyl Ester (CAPE), Resveratrol (RSV), and Genistein (GEN), exhibit promising anticancer properties, their clinical translation is hindered by poor solubility, chemical instability, rapid metabolism, and low bioavailability. As biodegradable polymers have been approved by the Food and Drug Administration (FDA), Poly (lactic-co-glycolic acid) (PLGA)-based Nanoparticles (NPs) represent a promising delivery platform to overcome these limitations by enabling both passive and active tumour targeting. METHODS: This review evaluates PLGA-based nanoparticle formulations for polyphenol delivery in cancer therapy, with an emphasis on single-drug delivery, co-encapsulation strategies (polyphenol-polyphenol and polyphenol-chemotherapeutic combinations), and functionalised targeted systems (e.g., folic acid-, transferrin-, ligand-, or peptide-mediated targeting). Studies conducted in two-dimensional (2D) and Three- Dimensional (3D) in vitro models, as well as in vivo models, are also discussed. RESULTS: Overall, PLGA NPs significantly improved the therapeutic activity of polyphenols by enhancing their stability, pharmacokinetics, and tumour accumulation via passive and active targeting mechanisms. Co-encapsulation and targeted delivery strategies show enhanced growth inhibition activity compared to free polyphenols and non-functionalised PLGA NPs. DISCUSSION: The activity of targeted PLGA co-delivery systems is attributed to the synergistic modulation of signalling pathways and improved intracellular accumulation via active targeting. This multifunctional delivery platform may serve as a strategy for combination cancer therapy by addressing the key pharmacokinetic limitations of polyphenols. CONCLUSION: Despite encouraging preclinical outcomes, several challenges remain, including batch-tobatch variability, large-scale production, long-term toxicity, immune responses, and clinical translation. Therefore, future studies should prioritise the development of stimuli-responsive, biomimetic, and personalised nanomedicine approaches to improve clinical applicability.