The Reality of Active Targeting in Nanomedicine: Promise Versus Performance.

Active targeting in nanomedicine aims to enhance therapeutic efficacy by functionalising nanocarriers with ligands that selectively bind biological targets. Despite extensive research, clinical translation has remained limited, with most approved systems relying on antibodies or passive delivery mechanisms rather than complex targeted nanoparticles. This perspective critically examines the gap between the conceptual promise of active targeting and its practical performance. Drawing comparisons with biological systems, we highlight that natural targeting relies on dynamic, multi-step and energy-dependent processes rather than simple ligand-receptor interactions. Current nanomedicine approaches are constrained by an oversimplified view of targeting, neglecting key factors such as multivalency, spatial organisation, kinetics and biological barriers. Future progress requires a shift towards systems-level design, integrating spatiotemporal control, adaptive materials and computational modelling. Ultimately, we propose a design-by-architecture paradigm, in which targeting is encoded into nanomaterial structure, enabling programmable and biologically guided delivery.