Targeted nanomedicines can improve drug solubility and stability, reshape pharmacokinetics, and enhance tolerability; however, precise delivery to the intended organ, recipient cell, and site of action remains difficult to achieve and verify. Following administration, dilution, component exchange, biomolecular corona formation, complement activation, blood-cell interactions, organ sequestration, intracellular trafficking, and degradation reshape formulation composition, biological interactions, and disposition. These processes transform the as-formulated synthetic identity into an acquired biological identity, while a therapeutically productive functional identity is established only when a pharmacologically competent cargo reaches the required compartment and engages with its intended molecular target. This review integrates systemic, tissue, cellular, and intracellular fate through three linked concepts: the carrier, therapeutic cargo, and analytical label, which are distinct fate objects that may follow divergent trajectories. Chemical modifications redistribute rather than eliminate delivery barriers, and organ accumulation is an intermediate endpoint rather than evidence of functional delivery. The review critically synthesizes evidence on blood-phase transformation, immune recognition and clearance, vascular and tissue transport, endosomal escape, organ-specific tropism, preclinical-to-human discordance, and emerging spatial and computational technologies. Particular emphasis is placed on PEG-lipid architecture, ionization behavior, supramolecular packing, ligand presentation, degradability, repeated administration, and manufacturing history. A minimum evidence framework is proposed that integrates integrity-sensitive tracing, recipient-cell localization, compartment-specific cargo release, molecular target engagement, safety assessment, repeated-dose performance, and validation in human-relevant systems. Treating in vivo fate as the organizing principle provides a rigorous basis for linking nanomaterial chemistry to pharmacologically productive exposure and clinical translation.
