Review Polyphenol-functionalized metal-organic frameworks: A strategic platform for advanced cancer drug delivery and synergistic therapy Alireza Hashemzadeh a,* , Yasir Qasim Almajidi b , Maher Abdulrazzaq Al-Hakeem b , Chou-Yi Hsu c , Prakhar Tomar d , Ahmed Hjazi e , Wesam R. Kadhum f , Abdul_Kareem Nasir g , Hayder Ridha-Salman h , Mohammad Ehsan Taghavizadeh Yazdi b,i ,* a Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran b Department of Pharmaceutics, College of Pharmacy, Alnahrain University, Baghdad, Iraq c Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan d Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura 140401, Punjab, India e Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia f Department of Pharmaceutics, College of Pharmacy, University of Kut, 52001 Wasit, Iraq g Mazaya University College, Dhiqar, Iraq h College of Pharmacy, Al-Mustaqbal University, 51001 Babylon, Iraq i Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran A R T I C L E INFO Keywords: Polyphenol-functionalized MOFs Cancer drug delivery pH-responsive release Synergistic therapy Targeted nanomedicine ABSTRACT Polyphenol-functionalized metal-organic frameworks (MOFs) have emerged as a revolutionary paradigm in cancer therapeutics, combining the structural versatility of MOFs with the bioactive and multifunctional prop- erties of polyphenols. This review comprehensively analyzes recent advancements in the design, synthesis, and biomedical applications of polyphenol-MOF hybrids for targeted drug delivery and synergistic cancer therapy. By leveraging polyphenols such as tannic acid, epigallocatechin gallate (EGCG), gallic acid, and polydopamine, these hybrid systems exhibit enhanced biocompatibility, pH-responsive drug release, and tumor-targeting ca- pabilities. Key innovations include the integration of polyphenol coatings or coordination networks with MOFs (e.g., ZIF-8, MIL-100, UiO-66) to enable stimuli-triggered cargo release, reactive oxygen species (ROS) genera- tion, and multimodal therapeutic effects (chemodynamic, photothermal, and sonodynamic therapy). Case studies highlight the role of polyphenol-MOF hybrids in overcoming limitations of conventional chemotherapy, such as poor drug solubility, off-target toxicity, and multidrug resistance. Furthermore, in vitro and in vivo evaluations demonstrate their efficacy in inducing apoptosis, depleting glutathione (GSH), and enhancing immunotherapy responses. Challenges such as scalability, long-term biosafety, and clinical translation are critically discussed, alongside future directions for engineering next-generation polyphenol-MOF nanoplatforms. This review un- derscores the transformative potential of polyphenol-MOF hybrids in precision oncology and advocates for their integration into mainstream cancer treatment strategies. 1. Introduction Cancer remains one of the most formidable global health challenges of our time, responsible for millions of deaths annually and imposing significant socioeconomic burdens worldwide[1–7]. Conventional therapeutic strategies, namely chemotherapy, radiotherapy, and sur- gery, have undoubtedly improved survival rates; however, each mo- dality faces substantial limitations. Chemotherapeutic agents, for example, are designed to eradicate rapidly dividing cells but often lack the specificity required to distinguish between malignant and healthy cells[8–17]. This non-specificity frequently results in severe systemic toxicities, as exemplified by the cardiotoxicity associated with doxoru- bicin and the neurotoxicity linked to paclitaxel[18]. In addition, multidrug resistance (MDR) remains a daunting challenge, with cancer cells acquiring various mechanisms such as drug efflux pumps and altered metabolic pathways that significantly reduce the efficacy of * Corresponding authors. E-mail addresses: hashemzadehalireza@gmail.com, hashemzadeha971@mums.ac.ir, a_hashemzadeh@sbu.ac.ir (A. Hashemzadeh), metyazdi@gmail.com (M.E.T. Yazdi). Contents lists available at ScienceDirect Materials Research Bulletin journal homepage: www.elsevier.com/locate/matresbu https://doi.org/10.1016/j.materresbull.2025.113778 Received 23 May 2025; Received in revised form 12 August 2025; Accepted 10 September 2025 Materials Research Bulletin 194 (2026) 113778 Available online 11 September 2025 0025-5408/© 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.