Targeted nanomedicine is often evaluated through evidence that a carrier reaches diseased tissue, accumulates within a lesion, or enters a target-cell population. These achievements are important, but each describes only one stage of a longer therapeutic problem. After lesion access, the carrier may acquire a different biological identity, enter the wrong cellular compartment, remain sequestered within endosomes or lysosomes, release its payload too early or too late, separate spatially from its payload, or generate intracellular exposure that is insufficient for pharmacodynamic activity. Even when these barriers are overcome, the resulting formulation may require dose intensity, administration procedures, toxicity surveillance, manufacturing complexity, or healthcare resources that constrain its clinical use. This Perspective examines the discordance between successful lesion-level targeting and clinically usable therapy. It distinguishes lesion accumulation, cellular entry, productive intracellular payload availability, pharmacodynamic action, toxicity, dose requirements, and treatment-delivery burden as separate evidentiary denominators. Particular attention is given to endosomal escape measurement, carrier–payload decoupling, and the possibility that improving one delivery property can worsen another. The central implication is that nanocarrier performance should be judged through linked but independently measured biological and practical outcomes. Lesion arrival can support therapeutic success, but it does not establish that the administered nanomedicine has delivered a usable treatment.
