This study presents the first evidence of RNA interference (RNAi) in humans from the systemic administration of small interfering RNAs (siRNAs) via targeted nanoparticles. The research involved a phase I clinical trial in patients with solid cancers, where siRNA was delivered using a nanoparticle-based system designed to target cancer cells. The nanoparticles, which contain a synthetic delivery system with a targeting ligand, were shown to accumulate in tumor tissue and induce RNAi, leading to the specific inhibition of the RRM2 gene, a known anti-cancer target. Tumor biopsies from melanoma patients revealed the presence of intracellularly localized nanoparticles, with levels correlating to the dose of the nanoparticles administered. Analysis of mRNA and protein levels showed a significant reduction in RRM2 expression, indicating that the siRNA was effectively silencing the target gene. Additionally, the presence of an mRNA fragment confirmed that siRNA-mediated mRNA cleavage occurred specifically at the predicted RNAi site in a patient who received the highest dose of the nanoparticles. The study also addresses the challenges of delivering siRNAs to specific tissues in mammals, highlighting the importance of targeted delivery systems. While previous studies have shown RNAi mechanisms in animals, this trial provides the first direct evidence of RNAi in humans from systemic siRNA administration. The results demonstrate that siRNA can be effectively delivered to human tumors using a targeted nanoparticle system, leading to gene-specific inhibition through the RNAi mechanism. The findings suggest that RNAi can be a viable therapeutic approach for treating solid cancers, with the potential for long-term effects due to the slow growth kinetics of the tumors involved. The study also outlines the methods used to detect the nanoparticles and confirm the RNAi mechanism, including immunohistochemistry, western blotting, and 5'-RLM-RACE PCR. The results provide important insights into the pharmacodynamics of siRNA delivery and the potential for RNAi-based therapies in human medicine.This study presents the first evidence of RNA interference (RNAi) in humans from the systemic administration of small interfering RNAs (siRNAs) via targeted nanoparticles. The research involved a phase I clinical trial in patients with solid cancers, where siRNA was delivered using a nanoparticle-based system designed to target cancer cells. The nanoparticles, which contain a synthetic delivery system with a targeting ligand, were shown to accumulate in tumor tissue and induce RNAi, leading to the specific inhibition of the RRM2 gene, a known anti-cancer target. Tumor biopsies from melanoma patients revealed the presence of intracellularly localized nanoparticles, with levels correlating to the dose of the nanoparticles administered. Analysis of mRNA and protein levels showed a significant reduction in RRM2 expression, indicating that the siRNA was effectively silencing the target gene. Additionally, the presence of an mRNA fragment confirmed that siRNA-mediated mRNA cleavage occurred specifically at the predicted RNAi site in a patient who received the highest dose of the nanoparticles. The study also addresses the challenges of delivering siRNAs to specific tissues in mammals, highlighting the importance of targeted delivery systems. While previous studies have shown RNAi mechanisms in animals, this trial provides the first direct evidence of RNAi in humans from systemic siRNA administration. The results demonstrate that siRNA can be effectively delivered to human tumors using a targeted nanoparticle system, leading to gene-specific inhibition through the RNAi mechanism. The findings suggest that RNAi can be a viable therapeutic approach for treating solid cancers, with the potential for long-term effects due to the slow growth kinetics of the tumors involved. The study also outlines the methods used to detect the nanoparticles and confirm the RNAi mechanism, including immunohistochemistry, western blotting, and 5'-RLM-RACE PCR. The results provide important insights into the pharmacodynamics of siRNA delivery and the potential for RNAi-based therapies in human medicine.