Metal-Organic Framework Nanoparticles Induced Non-Apoptotic Cell Death: Construction, Mechanisms, and Cancer Therapy

Tumor resistance to apoptosis remains a significant obstacle in cancer therapy. In recent years, non-apoptotic cell death modalities (such as ferroptosis, pyroptosis, and lethal autophagy) have emerged as promising strategies to overcome this resistance. However, most non-apoptotic cell death inducing drugs suffer from poor targeting, low tumor enrichment efficiency, and systemic toxicity, which limit their clinical application. Metal-organic framework nanoparticles (MOF NPs), which are composed of metal ions and organic linkers, offer a compelling solution due to their tunable structures and high drug loading capacity. These features enable them to enhance therapeutic efficacy by either efficiently delivering non-apoptotic inducers or acting as direct triggers for non-apoptotic cell death. This review systematically introduces the molecular mechanisms of ferroptosis, autophagy, pyroptosis, cuproptosis, and disulfidptosis. MOF NPs have unique advantages in inducing these mechanisms. The design strategies of MOF NPs based on these mechanisms (such as material composition, surface functionalization and responsive release) are mainly summarized. The applications and efficacy of them in the targeted induction of non-apoptotic cell death are subsequently reviewed. Finally, the challenges facing this field, including biosafety, large-scale preparation, and clinical application, and future development directions are discussed and prospected. • MOF NPs enhance therapy via targeted delivery or direct induction of non-apoptotic cell death. • Design strategies (composition, functionalization, release) of MOF NPs are outlined. • Molecular mechanisms of MOF NPs for inducing specific non-apoptotic death are detailed. • Challenges in efficient induction, biosafety, scale-up, and clinical translation are discussed.