Targeting Is Not Delivery: A Compartment-Resolved Theory of Nanomedicine Transport from Administration to Intracellular Drug Release

Nanomedicine is often evaluated through target affinity, tissue accumulation, cellular association, or carrier-triggered release, although none of these observations alone establishes that pharmacologically available drug has reached its intended site of action. This Original Transport Theory Article proposes Compartment-Resolved Delivery Theory as an organizing framework for separating the sequential transport states between administration and intracellular drug availability. The theory represents delivery as conditional movement through systemic, vascular, interstitial, cellular, vesicular, and pharmacological compartments, with competing losses possible at every transition. It distinguishes carrier location from payload state and treats overall delivery as dependent on stage-specific transfer efficiency rather than on a single targeting endpoint. Proposed quantitative metrics include available-dose fractions, transition efficiencies, retention and loss fractions, spatial coverage, payload integrity, and action-site availability. Validation would require matched measurements across adjacent compartments using physicochemical characterization, blood-interaction assays, pharmacokinetics, spatial biodistribution, vascular-crossing analysis, cellular trafficking measurements, release assays, and pharmacodynamic evidence. Concordance across in vitro systems, animal models, and human-relevant evidence would strengthen—but not independently prove—the theory’s applicability. Important boundaries include route dependence, disease heterogeneity, species-specific biological identity, analytical ambiguity, carrier–payload dissociation, and the possibility that optimizing one stage merely relocates the dominant bottleneck. The original contribution is a non-empirical, testable architecture for defining what delivery claims mean, identifying unmeasured losses, and directing validation toward the compartment that limits terminal drug availability. It is not a validated predictive model, clinical recommendation, regulatory standard, or universally applicable design rule.