Nonpersistent Nanoarchitectures Enhance Concurrent Chemoradiotherapy in an Immunocompetent Orthotopic Model of HPV+ Head/Neck Carcinoma

Cisplatin chemoradiotherapy (CRT) is the established standard of care for managing locally advanced human papillomavirus‐positive head/neck carcinoma. The typically young patients may suffer serious and long‐time side effects caused by the treatment, such as dysphagia, and hearing loss. Thus, ensuring a satisfactory post‐treatment quality of life is paramount. One potential replacing approach to the classical CRT involves the combination of standard‐dose radiotherapy and radiosensitizers such as noble metal nanoparticles (NPs). However, several concerns about size, shape, and biocompatibility limit the translation of metal nanomaterials to the clinical practice. Here, it is demonstrated that a new model of nonpersistent gold nanoarchitectures containing cisplatin (NAs‐Cluster‐CisPt) generates, in combination with radiotherapy, a significant in vivo tumor‐reducing effect compared to the standard CRT, achieving a complete tumor clearance in 25% of the immunocompetent models that persist for 60 days. These findings, together with the negligible amount of metals recognized in the excretory organs, highlight that the concurrent administration of NAs‐Cluster‐CisPt and radiotherapy has the potential to overcome some clinical limitations associated to NP‐based approaches while enhancing the treatment outcome with respect to standard CRT. Overall, despite further mechanistic investigations being essential, these data support the exploiting of nonpersistent metal‐nanomaterial‐mediated approaches for oral cancer management. Nonpersistent nanoarchitectures comprising cluster‐size gold demonstrate, in combination with radiotherapy, an outperforming therapeutic efficacy on orthotopic human papillomavirus‐positive head/neck squamous cell carcinoma immunocompetent murine models. This approach overcomes the clinical limitations associated to metal‐nanoparticle‐mediated radiotherapy while enhancing the treatment outcome with respect to the gold standard, opening new horizons in oral cancer management.