Key Tumor Responsive ZIF-8 Nanocarriers for Effective Anti-Cancer Therapeutics

Wenjing He,1 Haiyu Hu,1 Zhuochen Yu,1 Debiao Xiang,2, Lili Zhou1, 1School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 2Department of Pharmacy, The Third Hospital of Changsha, Changsha, 410035, People’s Republic of ChinaThese authors contributed equally to this workCorrespondence: Lili Zhou; Debiao Xiang, Email lilizhou@hnucm.edu.cn; debiao-xiang@cssdsyy.comAbstract: The intricate pathological features of the tumor microenvironment (TME) collectively contribute to therapeutic resistance, thereby substantially constraining the antitumor efficacy of conventional treatments. Zeolitic imidazolate framework-8 (ZIF-8), a pH-responsive metal-organic framework material, serves not only as an efficient drug delivery system but also actively participates in TME remodeling through the release of Zn2+ upon its degradation. This dual function as both a “carrier” and an “effector” offers a synergistic mechanism to mitigate therapeutic resistance. The article reviews recent research on ZIF-8, focusing on its role in targeted drug delivery and its transformation from a passive carrier to an active modulator of cellular environments. It examines how ZIF-8’s synthetic pathways and surface modifications aid in delivering various drugs and analyzes the molecular mechanisms by which released Zn2+ triggers stress responses and immune reactions. The article also discusses ZIF-8’s integration into theranostic platforms, its use in combination therapies, and the clinical translation challenges, including biosafety, reproducibility, and scalable production. This review aims to systematically synthesize existing knowledge across the aforementioned fields to establish a theoretical foundation for the design of next-generation ZIF-8 nanotheranostic systems and facilitate their progression toward clinical translation. The infographic illustrates the TME-responsive ZIF-8 nanoplatform for cancer therapy. It begins with the synthesis process, showing Zn superscript 2 plus and 2-Methylimidazole forming ZIF-8, which is then functionalized with drugs for EPR effect and ligand targeting. The acidic TME-responsive degradation leads to drug and Zn superscript 2 plus release. Combination therapies include chemotherapy, radiotherapy and immunotherapy. The dual ’Carrier-Effecter’ mechanism involves pH-responsive drug and Zn superscript 2 plus release targeting cancerous tumors, leading to DAMPs release, ICD, ROS production and activation of caspase and GSDMD. This process stimulates maturation and activation of DCs and mDCs, enhancing CD8 superscript plus T cells and CD4 superscript plus T cells. Theranostics involve imaging (MRI, PET) and image-guided therapy. The outlook emphasizes rational design, scalable synthesis, multifunctionality, clinical translation and personalized precision medicine.TME-responsive ZIF-8 nanoplatform: cancer therapy with theranostics and dual strategies.Keywords: tumor microenvironment, TME, pH-responsive, drug delivery, zinc ion interference