The National Cancer Institute (NCI) recognizes the potential of technologies based on the use of nanoparticles (NPs) in revolutionizing clinical approaches in the diagnosis and prognosis of cancer. Recent research suggests that once NPs come into contact with a biological fluid of cancer patients, they are covered by proteins, forming a "protein corona", composed of hundreds of plasma proteins. The concept of a personalized, disease-specific protein corona, demonstrating substantial differences in NP corona profiles between cancer and non-cancer patients has been introduced. We developed the design of an experimental prospective single center study with patients allocated in a 1:1:1 ratio of one of three arms: untreated patients with benign prostatic hyperplasia (BPH); untreated patients with non-metastatic prostate cancer (PCa); metastatic prostate cancer patients starting systemic therapies with new androgen-targeted agents or taxanes.. The protocol will aim to develop and implement sensitive nanotools with two distinct objectives. First, by designing NPs capable of selectively binding and detecting biomarkers in order to build a predictive diagnostic model to effectively discriminate between patient sera affected by BPH and PCa. Secondly, within the population with PCa, in case of initial advanced metastatic diagnosis, the objective will be to find biomarkers capable of predicting the response to systemic treatments to improve the precision and efficiency of monitoring treatment outcomes. For protein and metabolite corona experiments, we developed a cross-reactive sensor array platform with cancer detection capacity made of three liposomal formulations with different surface charges. For proteomics-NPs studies, proteins will be identified and quantified by nano-high-performance LC (nanoHPLC) coupled to MS/MS (nanoHPLC−MS/MS). Metabolites will be instead analyzed by an untargeted metabolomic approach.