Nanocarrier targeting has often been framed as a problem of increasing affinity for a disease-associated receptor or exploiting preferential vascular permeability. Clinical translation has exposed the incompleteness of that interpretation. A nanocarrier must survive systemic disposition, avoid or tolerate competing biological sinks, reach an accessible tissue compartment, retain a functional biological identity, release or present its payload appropriately, and produce a clinically relevant effect. These requirements are influenced by carrier composition, protein adsorption, immune recognition, administration route, particle dose, manufacturing process, disease context, and measurement scale. This State-of-the-Art Review examines how biodistribution studies, tumour and non-tumour targeting experiments, active-versus-passive targeting comparisons, barrier biology, dose-scaling studies, manufacturing investigations, and clinical experience have reshaped the targeting paradigm. The evidence supports a shift away from affinity-centred interpretation toward a multistage translational view in which tissue access and functional payload availability must be demonstrated independently of receptor recognition. Particular attention is given to why targeting effects observed in preclinical models contract in humans and why seemingly similar formulations may not remain biologically equivalent after scale-up. The review develops an evidence-bounded translational logic for distinguishing carrier accumulation, cellular access, payload availability, and clinical consequence without treating any one level as a surrogate for the others.
IJPRAS
