Synthesis of Tertiary Amine Assisted Cytocompatible Zn‐MOFs for Efficient Nucleic Acid Encapsulation and Delivery to Prostate Cancer Cells

Abstract Metal–organic frameworks (MOFs) are advanced hybrid materials with highly tunable structures, making them attractive candidates for biomedical applications, including nucleic acid delivery. Zeolitic imidazolate framework‐8 (ZIF‐8) is particularly promising due to its pH‐responsive degradation and biocompatibility. However, controlling the crystal phase and particle size of ZIF‐8 is critical for optimizing cellular uptake and therapeutic efficacy. Here, a one‐pot biomimetic mineralization strategy using a tertiary amine (e.g., triethylamine) to modulate the phase and size of DNA@ZIF biocomposites is reported. Without triethylamine, the resulting biocomposites form microscale carbonate‐phase particles, whereas the introduction of triethylamine induces the formation of nanoscale sodalite‐phase ZIF‐8. Moreover, triethylamine not only reduces particle size but also enhances the water stability and nucleic acid protection capabilities of the biocomposites. Triethylamine‐incorporated DNA@ZIF‐8 demonstrates negligible cytotoxicity and efficient gene delivery into prostate cancer cells compared to unmodified formulations. This study highlights the critical role of triethylamine as a modulating agent in fine‐tuning the crystallinity, particle size, and biological performance of DNA@ZIF, offering valuable insights into the design of advanced MOF‐based gene delivery systems for therapeutic applications.