Multi-Branched Au Nanodendrite@ZIF-67 Loaded with Tirapazamine for Tumor Microenvironment-Activated Disruption of Cancer Organoids

Tumor microenvironment-responsive nanomedicines offer significant advantages in enhancing treatment specificity and minimizing systemic toxicity. Nevertheless, the therapeutic efficacy of single-modality treatments is often limited by tumor heterogeneity, necessitating the development of multimodal nanoplatforms capable of leveraging multiple tumor microenvironment characteristics for efficient synergistic therapy. In this study, a multifunctional nanocomposite comprising cobalt zeolitic imidazolate framework-67-encapsulated Au nanodendrites coloaded with tirapazamine is developed for tumor-selective therapy. To address the inherent limitations of traditional preclinical models, human healthy and colorectal cancer organoids are utilized as advanced in vitro assessment platforms. Mechanistic studies revealed that multibranched Au nanodendrites disrupt cellular membrane integrity, whereas the acidic condition induces the degradation of the cobalt zeolitic imidazolate framework-67, facilitating targeted drug release. These combined actions synergistically amplify intracellular reactive oxygen species generation and disrupt mitochondrial membranes, leading to the selective elimination of tumor cells. This work presents a highly efficient, tumor microenvironment-responsive nanotherapeutic platform and demonstrates the critical value of organoid-based evaluation systems in advancing the clinical translation of targeted nanomedicines.