Metalloptosis: Metal Ions-Induced Programmed Cell Death Based on Nanomaterials for Cancer Therapy

Programmed cell death (PCD) is defined as regulated cell death controlled by an intracellular program. While apoptosis was once thought to be the only kind of PCD, current understanding has expanded to include other forms like pyroptosis, autophagy, and necroptosis. These processes, especially apoptosis and necroptosis, serve as natural defenses that restrict cancer cells from surviving and disseminating. However, cancer cells have evolved various strategies to evade PCD, including genetic mutations and epigenetic modifications in key modulators of PCD pathways. With the continuous development of nanotechnology, emerging nanomaterials (NMs) are considered to break through this bottleneck due to their intrinsic physicochemical properties. Especially, new kinds of cell death induced by NMs, such as ferroptosis, cuproptosis, and calcium overload, show gratifying potential in cancer therapy, which is closely linked to the role of metal ions. Additionally, other metal ions-induced cell death such as sodium and zinc have also emerged in an endless stream. Hence, we propose the term "metalloptosis" to describe cell death induced by metal ions and summarize its application in cancer therapy through NMs. This review will delve into the critical design principles for engineering NMs involved in metalloptosis and provide a comprehensive summary of current metal ions-mediated cancer therapies, focusing on nanoplatforms and their mechanisms of action. We hope that this review will provide a new perspective on metal ions-mediated cancer therapy based on nanotechnology.