The article provides an updated overview of the clinical landscape of nanoparticle drug delivery systems, highlighting recent advancements and clinical trials. Since the last review in 2016, three new nanomedicines have been approved: VYXEOS, Patisiran/ONPATTRO, and NBTRX3/Hensify. VYXEOS, a combination chemotherapy nanoparticle, received FDA approval for treating acute myeloid leukemia. Patisiran/ONPATTRO, an siRNA-delivering lipid-based nanoparticle, was the first FDA-approved RNAi therapeutic. NBTRX3/Hensify, a hafnium oxide nanoparticle, received CE Mark approval for treating locally advanced soft tissue sarcoma. Additionally, over 75 new clinical trials have started for previously unapproved nanoparticles, and 18 new nanoparticles have entered clinical trials since 2016, primarily for cancer treatment. The article also discusses the challenges and limitations of nanoparticle drug delivery systems, emphasizing the need to address biological, technological, and clinical issues to ensure consistent clinical impact. Despite these challenges, the field of nanoparticle drug delivery continues to make significant progress, offering new treatment modalities and improving human health.The article provides an updated overview of the clinical landscape of nanoparticle drug delivery systems, highlighting recent advancements and clinical trials. Since the last review in 2016, three new nanomedicines have been approved: VYXEOS, Patisiran/ONPATTRO, and NBTRX3/Hensify. VYXEOS, a combination chemotherapy nanoparticle, received FDA approval for treating acute myeloid leukemia. Patisiran/ONPATTRO, an siRNA-delivering lipid-based nanoparticle, was the first FDA-approved RNAi therapeutic. NBTRX3/Hensify, a hafnium oxide nanoparticle, received CE Mark approval for treating locally advanced soft tissue sarcoma. Additionally, over 75 new clinical trials have started for previously unapproved nanoparticles, and 18 new nanoparticles have entered clinical trials since 2016, primarily for cancer treatment. The article also discusses the challenges and limitations of nanoparticle drug delivery systems, emphasizing the need to address biological, technological, and clinical issues to ensure consistent clinical impact. Despite these challenges, the field of nanoparticle drug delivery continues to make significant progress, offering new treatment modalities and improving human health.