Ligand–receptor affinity is often treated as the defining variable of active nanocarrier targeting, yet affinity can operate only after a carrier remains systemically available, reaches an accessible vascular segment, crosses or engages the endothelial barrier, traverses tissue, retains a biologically exposed ligand, and encounters a sufficiently available receptor. This Perspective argues that these preceding events should be treated as conditional access gates rather than background pharmacokinetics. Evidence from dose-dependent clearance, vessel-resolved permeability, transendothelial transport, tumour exit, interstitial pressure, macrophage redistribution, protein-corona remodeling, and single-particle ligand measurements shows that failure can arise before molecular recognition is possible. We therefore distinguish intrinsic affinity from biological access, functional ligand availability, receptor encounter, avidity, internalization, and payload availability. The resulting access-before-affinity interpretation is proposed as an evidence-bounded diagnostic logic, not as a universal quantitative law. It predicts that apparent targeting failure should first be localized to the earliest limiting biological compartment before affinity is optimized or blamed.
IJPRAS
