Targeted Delivery of Chemotherapeutics to Tumors: Design Principles, Barriers, and Future Directions

Conventional chemotherapy frequently causes uneven drug distribution and systemic toxicity due to inadequate in vivo selectivity. Passive targeting strategies, such as the enhanced permeability and retention effect, can no longer guarantee effective drug accumulation within tumor tissues. The success of active targeted chemotherapy cannot be simplified to a basic “ligand-drug” binding model, but relies on the coordinated regulation of multiple processes, including drug distribution, tumor penetration, cellular internalization, and intracellular processing. From a design-oriented perspective, this review elaborates on the core design logic of targeted chemotherapy delivery and highlights that target expression and accessibility, pharmacokinetic characteristics of targeting moieties, payload compatibility, and drug release mechanisms serve as critical determinants of therapeutic outcomes. Furthermore, this review summarizes and evaluates current mainstream targeted chemotherapy delivery platforms, including antibody-based, aptamer-based, small-molecule, peptide, and hybrid delivery systems. Finally, future research directions for targeted chemotherapy development are prospected. Rather than pursuing a single optimal delivery platform, a problem-oriented design strategy is proposed. The design of next-generation delivery systems requires an optimal balance among targeting construct size, in vivo drug exposure, and tissue permeability, as well as payload release profiles, based on the dominant transport limitations of specific tumor microenvironments.