Ancient and Emerging Nanostructures for Innovations to Fight Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) remains a major global health challenge due to its aggressive behavior, late-stage diagnosis, and high incidence of therapy resistance. At the cellular level, these clinical limitations are driven by profound alterations in oncogenic signaling, stress adaptation, DNA damage response pathways, and immune regulation within the tumor microenvironment. Advances in nanotechnology offer powerful opportunities to address these challenges by enabling targeted interference with cellular processes that govern tumor growth, survival, and therapy resistance. "Ancient" (i.e., established, long-studied) nanostructures, including mineral-based nanoparticles, natural biopolymers, and plant-derived nanovesicles, provide inherently biocompatible and bioactive platforms capable of modulating cellular signaling, redox balance, and immune responses. In parallel, emerging nanosystems-such as nanobodies, engineered exosomes, DNA origami, and stimuli-responsive smart nanoparticles-allow precise molecular targeting, controlled cargo release, and direct manipulation of intracellular pathways and intercellular communication. This manuscript synthesizes historical and contemporary developments in nanostructure design, highlighting how the integration of ancient materials with advanced nanotechnology can reshape therapeutic strategies for HNSCC. By targeting key cellular and microenvironmental processes, including DNA damage response signaling, redox homeostasis, immune regulation and stress-adaptive survival mechanisms, rather than drug delivery alone, these integrated nano-platforms offer promising avenues to overcome resistance mechanisms, reprogram the tumor microenvironment, and improve therapeutic precision and patient outcomes.