Metal nanoparticles have demonstrated a number of promising behaviors for diagnosis and treatment of many neoplasms. The best physical and physiological features have been observed for nanostructures larger than 20 nm. Unluckily, such size causes their accumulation in excretory system organs, increasing the likelihood of toxicity and interference with common medical diagnoses. Thus, one of the major concerns for the clinical translation of such nanostructures is related to their persistence in organisms. Metal nanoparticles' size-reduction to few nanometers make possible their excretion by the renal pathway. However, most of the functionalities are lost or severely altered jeopardizing possible applications. A suitable approach to jointly combine the appealing behavior of metal nanoparticles with their organism excretion is by degradable nano-architectures (NAs). Composition: ultrasmall metal nanoparticles aggregated by modified-polymers and embedded in tailored hollow silica nanocapsules. NAs can: i) reach the target in the organism by passive or active accumulation, ii) exploit their therapeutic/diagnostic action, and iii) biodegrade in 48h to renal clearable building blocks, such as polymers, ultrasmall metal nanoparticles and silicic acid. The objective of this project is to transfer solid living cells results to in vivo investigations to unlock a new paradigm for nanomedicine. It will be demonstrated the: i) degradation and excretion of gold-based nano-architectures by the renal pathway, and ii) their efficiency as passive and active theranostics by combining photoacoustic imaging and drug delivery behaviors. The target will be head and neck squamous cell carcinomas (HNSCC), aggressive and hard to surgery neoplasms. Expected intermediate outcomes are explorations of other non-invasive diagnostic techniques and synergistic co-therapy applications. NAs will be massively produced by employing my patented protocol and fully characterized by standard techniques. Living 2D and 3D cell experiments will be performed by confocal microscopy and cryo-TEM measurements. NAs will be investigated in health and orthotopic HNSCC xenograft murine models by both non-invasive imaging and destructive techniques, in order to evaluate their theranostics and co-theranostics efficacy, biodistribution, and excretion in urines. This approach which combines metal nanoparticles to their excretion will allow to overcome the issue of accumulation while maintaining all their advantages. The development of this innovative theranostic will lead to transfer inorganic nanomaterials to clinic. In the next future, the extreme versatility of these nano-architectures might allow to address a wide range of neoplasms. This shall be the way to pursue in order to treat carcinomas in a less invasive and more efficient manner.