Engineering carrier systems in targeted alpha therapy: Overcoming nuclear recoil and radiolysis for safer translation

Targeted alpha therapy (TAT) has emerged as a highly potent modality in precision oncology. However, its clinical translation is hindered by unique radiobiological and pharmacological challenges. This review provides a structured overview of carrier systems used in TAT, including small molecules, peptides, antibodies and their fragments, and nanocarriers. How carrier properties shape pharmacokinetics, tumor penetration, and therapeutic index is discussed, with a focus on two principal challenges: nuclear recoil and radiolysis. Strategies to mitigate these effects—including chelator optimization, ligand stabilization, nanoparticle encapsulation, and radical scavenger incorporation—are critically evaluated. Beyond molecular design, translational aspects are summarized, including theranostic applications, pretargeting strategies, combination regimens, and recent clinical trial outcomes. Finally, practical barriers related to isotope supply, manufacturing, and regulatory constraints are highlighted. By integrating these perspectives, this review outlines both the opportunities and constraints that guide the rational design and clinical advancement of next-generation TAT radiopharmaceuticals.