Next-Generation Hybrid Nano-formulations for Polyphenolic Nutraceuticals in Cancer Therapy: An Overview

Cancer remains the leading cause of death globally. Conventional cancer treatments are capable of effectively targeting tumor cells; however, they might trigger immunosuppression, multidrug resistance, and harm healthy cells. Polyphenols are nutraceuticals-based naturally occurring phytochemicals with promising nutraceutical, antioxidant, antineoplastic, anti-inflammatory, and free-radical scavenging properties. This review highlights strategies for encapsulating them within hybrid nanostructures to overcome their limitations of poor aqueous solubility, low bioavailability, and lack of target specificity. Moreover, it provides insights into the major molecular signaling pathways underlying the anticancer activity of polyphenols and their hybrid nanoformulations.

A comprehensive literature review was conducted from accredited databases, including Google Scholar, Scopus, PubMed, and Web of Science (1996 to present), on naturally occurring polyphenols and their encapsulation into hybrid formulations. Emphasis was placed on hybrid nanocarriers, with keywords including dendrimers, micelles, polymers, mesoporous silica, gold nanoparticles, and carbon nanotubes, prepared by combining inorganic nanoparticles with organic lipids or polymers.

Polyphenols exhibit promising nutraceutical, antioxidant, antineoplastic, anti-inflammatory, and freeradical- scavenging properties, along with significant potential to modulate oxidative stress, apoptosis, metabolism, proliferation, inflammation, angiogenesis, and tumor signaling pathways, including MAPK, PI3K/Akt/ mTOR, Wnt/β-catenin, and STAT3. Encapsulation of polyphenols into Hybrid Nanoformulations (HNs) yields a synergistic system that significantly improves stability, bioavailability, targeted delivery, and effectiveness in cancer treatment. HNs further demonstrated the potential to integrate the advantages of multiple delivery systems, thereby improving therapeutic outcomes and reducing systemic toxicity.

The available studies highlight hybrid nanoformulations as a versatile platform to maximize the therapeutic potential of polyphenols in cancer treatment. Integrating the advantages of different nanocarrier systems offers new strategies for developing more effective and targeted cancer therapies.

This review presents a promising approach to cancer therapy by integrating polyphenols into hybrid nanoformulations, addressing key limitations of conventional polyphenol delivery and thereby enhancing their anticancer potential through multiple molecular pathways. However, despite the encouraging benefits, no polyphenol-based nanoformulation has yet been approved by the US FDA for cancer therapy due to limited clinical evidence, challenges associated with large-scale manufacturing, regulatory concerns, and long-term safety assessment. Further preclinical validation and clinical studies are required to facilitate the successful application of polyphenolic hybrid nanoformulations in cancer management.