Synergistic combined treatments are currently practiced in clinics for the management of several neo-plasms. While surgery, radiotherapy, and chemotherapy remain as the standards of care for monomodal and co-treatments, emerging modalities like hyperthermia (HT) demonstrate promising features as (neo) adjuvant, particularly for recurrent cancers. However, the clinical relevance of HT is still debated due to a number of challenges, such as tumor specific temperature increase, uneven heating of the target, and the lack of agents that concurrently execute HT in combination with radioand/or chemotherapy. Here, the application of non-persistent ultrasmall-in-nano gold architectures for synergistic chemophotothermal treatment of head and neck squamous cell carcinomas (HNSCCs) is presented. The nano architectures are composed of excretable narrow near-infrared (NIR)-absorbing gold ultrasmall nanoparticles and an endogenously double controlled cisplatin prodrug. The efficiency of the nano-architectures is evaluated on three-dimensional (3D) models of HNSCCs with positive or negative human papillomavirus (HPV) status. The combined treatment causes a more pronounced antitumor action on HPVpositive HNSCCs. Overall, the findings demonstrate the potential clinical relevance of translatable noble metal-based synergistic treatments in tumors management. (c) 2020 Elsevier Inc. All rights reserved.