Nanomaterial-Driven Regulated Cell Death: Mechanistic Insights and Novel Strategies for Tumor Therapy

Yiheng Luo,1,2,* Xundong Lin,1,2,* Chuyu Su,1 Zesen Zheng,1 Yuezi Li,1 Weihong Guo,2 Xiaoli Feng1 1Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weihong Guo, Email [email protected] Xiaoli Feng, Email [email protected]: The rapid development of nanomaterials (NMs) and nanotechnology has profoundly impacted the biomedical field. Due to their unique physicochemical properties, NMs can interact with biological molecules, including proteins and DNA, to induce regulated cell death (RCD). Recent studies have demonstrated that NMs trigger RCD by promoting reactive oxygen species generation, activating signaling proteins, and disrupting intracellular ion homeostasis. Among the various forms of RCD, necroptosis, pyroptosis, ferroptosis, and cuproptosis have garnered significant research attention. Increasing evidence suggests that these emerging RCD pathways are crucial for tumor proliferation and migration, tumor microenvironment (TME) remodeling, and drug resistance mitigation. Accordingly, leveraging NM-driven RCD’s effects in designing multifunctional drug delivery systems holds great promise for cancer therapy. NMs can also serve as versatile drug carriers in synergistic treatments with targeting agents, photothermal/photodynamic therapy, and immunomodulators, thereby overcoming the limitations of conventional treatments. Collectively, this review systematically summarizes recent advancements in NM-induced RCD in cancer cells and discusses the diverse roles of RCD in tumor pathology. We highlight the innovative potential of NMs in inducing RCD through precise targeting and synergistic therapy, offering novel strategies to overcome tumor resistance and reshape the immunosuppressive TME. Keywords: nanomaterials, regulated cell death, cuproptosis, tumor drug resistance, tumor microenvironment