DNA self-assembly-mediated high drug-antibody ratio ADC platform for targeted tumor therapy and imaging

Antibody-drug conjugates (ADCs) achieve therapeutic effects through toxin delivery inside cells, targeting high-abundance antigens. However, tumor heterogeneity and the low abundance of tumor-specific antigens underscore the urgent requirement for developing a flexible, multifunctional, and high-capacity drug-delivery platform. The current study developed a self-assembled ADC platform called the high drug–antibody-ratio ADC (HD-ADC). Cytotoxic payloads were efficiently conjugated into a 12-arm deoxyribonucleic acid (DNA) branched junction via DNA-mediated precise self-assembly to achieve a high drug–antibody ratio (DAR). Anti-EGFR HD-ADC showed strong efficacy in causing cytotoxicity and suppressing tumor growth in an A431 xenograft mouse model. Furthermore, the Cy5-conjugated HD-ADC platform was a simple and effective method for improving fluorescent signal detection, enabling the detection of targets—such as neoantigens—with ultralow-expression levels. The HD-ADC platform supports the assembly of various functional components, providing the foundation for usage across multiple antibody-mediated targeted therapies and diagnostics. • Self-assembled High Payload-Antibody-Ratio ADC/AFC platform via precise DNA pairing. • HD-AFC enables tumor-specific imaging through targeting low abundant neoantigen. • HD-ADC/AFC, with cytotoxin/fluorophore, exhibits high potency in xenograft models.