The development of nanoparticles (NPs) has expanded into a broad range of clinical applications, aiming to overcome the limitations of free therapeutics and navigate biological barriers. Precision therapeutics, which personalize interventions to enhance therapeutic efficacy, have also emerged as a significant approach. However, current NP development often focuses on a one-size-fits-all solution. This review discusses advanced nanoparticle designs that can be optimized for personalized drug delivery, moving towards the era of precision medicine. It highlights the potential of engineered NPs to improve stability, solubility, and transport across membranes, as well as their ability to prolong circulation times. The review covers the challenges of translating NP research from animal models to human clinical trials, emphasizing the need to address patient heterogeneity and biological barriers. It also explores the use of biomaterials and biomedical engineering innovations to overcome these barriers, particularly in the context of precision medicine. The review discusses the progress made in nanomedicine, the biological barriers that have limited NP applications, and rational NP designs aimed at overcoming these obstacles. It further examines the distribution and delivery trends in NP research, focusing on the impact of NP characteristics on therapeutic responses. The review concludes by discussing the potential of combining NPs with precision medicine to advance both fields, improve patient outcomes, and accelerate the clinical translation of nanomaterials.The development of nanoparticles (NPs) has expanded into a broad range of clinical applications, aiming to overcome the limitations of free therapeutics and navigate biological barriers. Precision therapeutics, which personalize interventions to enhance therapeutic efficacy, have also emerged as a significant approach. However, current NP development often focuses on a one-size-fits-all solution. This review discusses advanced nanoparticle designs that can be optimized for personalized drug delivery, moving towards the era of precision medicine. It highlights the potential of engineered NPs to improve stability, solubility, and transport across membranes, as well as their ability to prolong circulation times. The review covers the challenges of translating NP research from animal models to human clinical trials, emphasizing the need to address patient heterogeneity and biological barriers. It also explores the use of biomaterials and biomedical engineering innovations to overcome these barriers, particularly in the context of precision medicine. The review discusses the progress made in nanomedicine, the biological barriers that have limited NP applications, and rational NP designs aimed at overcoming these obstacles. It further examines the distribution and delivery trends in NP research, focusing on the impact of NP characteristics on therapeutic responses. The review concludes by discussing the potential of combining NPs with precision medicine to advance both fields, improve patient outcomes, and accelerate the clinical translation of nanomaterials.