Dual-payload antibody–drug conjugates: Taking a dual shot

Antibody-drug conjugates (ADCs) enable the precise delivery of cytotoxic agents by conjugating small-molecule drugs with monoclonal antibodies (mAbs). Over recent decades, ADCs have demonstrated substantial clinical efficacy. However, conventional ADCs often encounter various clinical challenges, including suboptimal efficacy, significant adverse effects, and the development of drug resistance, limiting their broader clinical application. Encouragingly, a next-generation approach—dual-payload ADCs—has emerged as a pioneering strategy to address these challenges. Dual-payload ADCs are characterized by the incorporation of two distinct therapeutic payloads on the same antibody, enhancing treatment efficacy by promoting synergistic effects and reducing the risk of drug resistance. However, the synthesis of dual-payload ADCs is complex due to the presence of multiple functional groups on antibodies. In this review, we comprehensively summarize the construction strategies for dual-payload ADCs, ranging from the design of ADC components to orthogonal chemistry. The subsequent sections explore current challenges and propose prospective strategies, highlighting recent advancements in dual-payload ADC research, thereby laying the foundation for the development of next-generation ADCs.