Gold- and Platinum-Peptide Bioconjugates in Cancer Therapy: Recent Advances and Future Directions

Background: Metal-based anticancer drugs, particularly platinum and gold complexes, play a central role in chemotherapy but are often limited by systemic toxicity, resistance, and suboptimal selectivity. Peptide conjugation has emerged as a versatile strategy to modulate the pharmacokinetic and biological properties of metal complexes, enabling targeted delivery, improved uptake, and controlled activation. This review aims to critically analyze platinum- and gold-peptide bioconjugates in cancer therapy, focusing on directly reactive metal complexes and redox-activated prodrug systems. Methods: Relevant literature from the past two decades was surveyed across major scientific databases, focusing on the design, conjugation strategies, biological activity, and mechanisms of action of Pt- and Au-peptide bioconjugates. Results: Reviewed studies reveal distinct behavior for platinum- and gold-based systems. Pt(II)-peptide conjugates primarily retain DNA-reactive interaction, with peptides mainly enhancing cellular uptake, selective targeting and solubility, although improved cytotoxicity is not consistently achieved. In contrast, Pt(IV)-peptide conjugates function as prodrugs, where axial peptide functionalization allows greater structural versatility and sometimes improved selectivity, with therapeutic efficacy strongly depending on intracellular reduction kinetics. Au(I)-peptide conjugates act as directly reactive species targeting thiol- and selenol-containing proteins, whereas Au(III) bioconjugates often behave as redox-activated prodrugs, with peptide conjugation influencing stability and cellular fate. Conclusions: Overall, peptide conjugation represents a powerful but non-trivial approach for optimizing metal-based anticancer agents. The success of metal-peptide bioconjugates critically depends on balancing peptide-mediated delivery with the intrinsic reactivity and activation pathways of the metal center. A function-guided design of bioconjugates is essential to achieve genuine selectivity and therapeutic benefit.