Antibody–drug conjugates for infectious and neglected tropical diseases: chemical design principles, target biology, and translational challenges

Antibody-drug conjugates (ADCs) are established precision treatments in oncology. Nevertheless, their application to infectious diseases and neglected tropical diseases (NTDs) is still an emerging field. In contrast to cancer cells, pathogens exhibit dynamic surface features and distinct intracellular environments, necessitating a complete redesign of the ADC architecture. This review combines chemical concepts and biological insights to outline a "pathogen-centric" framework for bacterial, viral, and parasite illnesses. We analyze target selection across various diseases, emphasizing structural accessibility and antigen stability as critical factors. A comprehensive evaluation of ADC chemical architecture is provided, focusing on linkers that respond to pathogen-specific enzymatic or environmental triggers, alongside a range of non-cytotoxic payloads, notably redox-active metallo-drugs designed to overcome antimicrobial resistance. We rigorously analyze the shift from empirical screening to AI-enhanced and structurally-informed design processes. Lastly, we look at the particular translation concerns in this field, such as the Payload Paradox and the complications that come with internalization. We discuss also sustainable biomanufacturing methods that will ensure equitable and fair access to the products. This study offers a chemistry-based framework that outlines the essential ideas required for the advancement of antibody-drug conjugates (ADCs) as targeted anti-infectives for major global infections.