The article reviews the factors that influence the clearance and biodistribution of polymeric nanoparticles, which are crucial for their therapeutic efficacy. Key factors include interactions with biological barriers, tunable nanoparticle parameters such as composition, size, core properties, surface modifications (pegylation and surface charge), and targeting ligand functionalization. These factors significantly affect the biodistribution and blood circulation half-life of nanoparticles by reducing nonspecific uptake, delaying opsonization, and enhancing tissue-specific accumulation. The review also discusses the impact of physiological tissue defects, such as abnormal neovascularization, on nanoparticle delivery and the role of poly(ethylene glycol) (PEG) in reducing protein adsorption and improving nanoparticle circulation. Additionally, it explores the effects of nanoparticle size, core composition, surface functionality, and active targeting on biodistribution and therapeutic outcomes. The conclusion emphasizes the importance of precise control over nanoparticle properties to enhance their therapeutic potential.The article reviews the factors that influence the clearance and biodistribution of polymeric nanoparticles, which are crucial for their therapeutic efficacy. Key factors include interactions with biological barriers, tunable nanoparticle parameters such as composition, size, core properties, surface modifications (pegylation and surface charge), and targeting ligand functionalization. These factors significantly affect the biodistribution and blood circulation half-life of nanoparticles by reducing nonspecific uptake, delaying opsonization, and enhancing tissue-specific accumulation. The review also discusses the impact of physiological tissue defects, such as abnormal neovascularization, on nanoparticle delivery and the role of poly(ethylene glycol) (PEG) in reducing protein adsorption and improving nanoparticle circulation. Additionally, it explores the effects of nanoparticle size, core composition, surface functionality, and active targeting on biodistribution and therapeutic outcomes. The conclusion emphasizes the importance of precise control over nanoparticle properties to enhance their therapeutic potential.