Synergistic targeting systems for cancer precision medicine: co- and sequential binding to multiple tumor biomarkers.

Cancer poses a crucial risk to human health because of its complexity and heterogeneity. Precision medicine has been widely noticed as an emerging concept, which brings great opportunities to improve cancer diagnosis and treatment. Here, tumor biomarkers and corresponding diseased-site targeting strategies are emphasized, recognition ligands with high specificity and affinity are summarized and the common and creative approaches of precision medicine are discussed. Further, precision targeting systems (PTS) based on different numbers of tumor biomarkers, including single-, dual- and triple biomarker-based PTS, are reviewed. Based on the binding of multiple recognition probes to different markers especially in a sequential manner, the advantages of synergistic targeting strategies in cancer diagnosis and treatment are separately highlighted. In addition, the application of single- and multi-marker-based PTS in detecting the expression level of specific molecules, inducing the dysfunctional species within subcellular locations (e.g., nucleus and mitochondria) is summarized. Finally, the challenges and future perspective of PTS based on multiple biomarkers are discussed. The review indicates that further improvement of precision medicine relies on new breakthroughs in the discovery of biomarkers exclusive to diseased cells and their ingenious combination, which will become a cornerstone of biomedical studies and clinical precision medicine. STATEMENT OF SIGNIFICANCE: To a large degree, significant advancement in precision medicine is highly dependent on the development of precision targeting systems (PTS) based on the recognition of multi-ligands to different targets, coupled with a deep understanding of their operational mechanisms for tumor cell recognition and drug delivery. This review summarizes common tumor biomarker receptors and their specific recognition ligands, the design of targeted delivery systems based on single or multiple tumor biomarkers (especially sequential targeting systems), the molecular mechanisms for their operation, and their applications within subcellular structures. These innovations deepen our understanding of the design and operational mechanisms of PTS and reveal their potential to overcome tumor heterogeneity. By emphasizing the unique advantages of precision targeting systems, this review is expected to efficiently highlight the precision medicine of cancer patients and offered a new opportunity for cancer prevention, treatment, and prognosis in a precise manner.