For the frist time, we revealed the formation of EGCG oxidation self-assembled nanoparticles (ENPs) and systemically investigated the biological characteristics of ENPs and EGCG in the REDOX activity as well as in the biosafety in vitro and in vivo.

Cancer remains a highly lethal disease globally. The approach centered on REDOX-targeted mitochondrial therapy for cancer has displayed notable benefits. Plant polyphenols exhibit strong REDOX and anticancer properties, particularly by affecting mitochondrial function, yet their structural instability and low bioavailability hinder their utility. To overcome this challenge, researchers have utilized the inherent physical and chemical characteristics of polyphenols and their derivatives to develop innovative nanomedicines for targeting mitochondria. This review examines the construction strategies and anticancer properties of various types of polyphenol-based biological nanomedicine for regulating mitochondria in recent years, such as polyphenol self-assembly, metal–phenol network, polyphenol–protein, polyphenol–hydrogel, polyphenol–chitosan, and polyphenol–liposome. These polyphenolic nanomedicines incorporate enhanced features such as improved solubility, efficient photothermal conversion capability, regulation of mitochondrial homeostasis, and ion adsorption through diverse construction strategies. The focus is on how these polyphenol nanomedicines promote ROS production and their mechanism of targeting mitochondria to inhibit cancer. Furthermore, it delves into the benefits and applications of polyphenolic nanomedicine in cancer treatments, as well as the challenges for future research.

The imbalance of the renin–angiotensin system (RAS), characterized by the overactivation of the pro-tumor ACE/AngII/AT1R axis, is closely linked to tumor growth, angiogenesis, metastasis, and poor prognosis. Natural polyphenols, such as EGCG and resveratrol, exert anti-cancer effects by dual-regulating RAS: they inhibit the pro-tumor axis by blocking renin, ACE activity, and AT1R expression, while simultaneously activating the protective ACE2/Ang(1-7)/MasR axis. Furthermore, polyphenols and their autoxidation products (e.g., EAOP) modify thiol-containing transmembrane proteins (such as ADAM17 and integrins) and interact with RAS components, further disrupting oncogenic pathways (including MAPK and PI3K/Akt/mTOR) to induce apoptosis, suppress invasion, and reduce oxidative stress. Notably, EAOP exhibits stronger RAS-modulating efficacy than its parent polyphenols. However, challenges such as low bioavailability, insufficient targeting, and limited clinical evidence impede their application. This review provides a comprehensive overview of the anti-cancer mechanisms of polyphenols through RAS regulation, discusses the associated challenges, and proposes potential solutions (including nanodelivery and structural modification) and strategies to advance natural product-based adjuvant treatments.

Silver nanoparticles (AgNPs) have emerged as a promising nanoplatform for oncological intervention, yet their clinical translation is severely hampered by systemic toxicities associated with high effective doses, while the underlying mechanisms governing their interactions with cancer cell pro-survival cascades remain poorly defined. In this study, we synthesized and fully characterized green tea polyphenol (-)-Epigallocatechin-3-gallate (EGCG)-derived silver nanoparticles (EAgNPs), in which EGCG acts as the reducing and capping agent. EAgNPs were confirmed to be highly dispersed, stable metallic silver particles with a primary size range of 4–7.6 nm. Subsequent mechanistic investigations performed on Tca8113 human tongue cancer cells revealed distinct dose-dependent anticancer action modes of EAgNPs: the 100 μM lethal dose effectively triggered robust apoptosis via potently suppressing the activity of key antioxidant selenoenzymes, including thioredoxin reductase and glutathione peroxidase (GPx), and multiple drug resistance proteins. Notably, even under this lethal treatment condition, Tca8113 cells still initiated theNrf2-associated antioxidant response characterized by 2-fold glutathione elevation and 25-fold heme oxygenase-1 upregulation. The 30 μM low-dose EAgNPs, however, failed to produce salient cytotoxicity, as they moderately inhibited GPx activity while comprehensively activating the integrated cancer cell defense network, including glutathione accumulation, Nrf2-associated antioxidant protein induction, and upregulation of a full panel of drug resistance proteins. Interestingly, the combination of 30 μM EAgNPs with the glutathione synthesis inhibitor L-buthionine-sulfoximine further enhanced selenoenzyme GPx inhibition and completely abrogated all above-mentioned inducible anti-apoptotic responses, resulting in multi-target disruption of the cytoprotective system and strongly enhanced apoptosis induction. Our findings demonstrate that this combinatorial strategy effectively lowers the therapeutic dose threshold of EAgNPs by disabling cancer cell adaptive resistance, providing a low-toxicity, translationally feasible approach for localized oral cancer treatment.