Dietary Polyphenol-Based, Tumor Microenvironment-Responsive Carrier-Free Nanoplatforms for Synergistically Enhanced Tumor-Targeted Therapy

Cancer remains a leading global cause of morbidity and mortality. Natural polyphenols show potent antitumor activity—driven by antioxidant, anti-angiogenic, and epigenetic regulatory effects—but their clinical use is hindered by poor aqueous solubility, chemical instability in physiological conditions, low oral bioavailability, and insufficient tumor accumulation. In response, carrier-free nanomedicines, self-assembled nanostructures formed exclusively from therapeutic polyphenols without exogenous excipients or polymeric carriers, have emerged as a paradigm-shifting delivery strategy. This review provides a rigorous, mechanism-informed evaluation of how dietary polyphenol (e.g., epigallocatechin gallate [EGCG], curcumin, resveratrol, mangiferin, and quercetin)-based carrier-free smart nanoplatforms, by virtue of their tunable supramolecular architecture, enhanced stability, prolonged circulation, and passive/active tumor targeting capabilities, strategically exploit and amplify these antitumor mechanisms to confront the heterogeneity, adaptability, and therapeutic resistance inherent in malignant pathophysiology. Crucially, this review bridges translational gaps by explicitly linking molecular-level mechanistic insights to rational nanomaterial design principles and quantifiable preclinical/clinical therapeutic outcomes. Finally, it critically appraises persistent scientific, manufacturing, and regulatory challenges, including scalability, batch-to-batch reproducibility, long-term colloidal stability, in vivo fate mouthline standardized efficacy/safety assessment, and outlines forward-looking perspectives for accelerating the clinical realization of polyphenol-based carrier-free smart nanotherapeutics.