High-payload antibody-oligonucleotide-drug conjugates (AODC) for targeted tumor chemo-immunotherapy

Antibody-drug conjugates (ADCs) have emerged as powerful targeted therapeutics, yet their clinical performance remains constrained by the limited payload capacity achievable with conventional small-molecule drugs. Here we introduce antibody-oligonucleotide drug conjugates (AODCs), a programmable conjugate modality enabled by oligonucleotide prodrug architectures. Distinct from conventional antibody-oligonucleotide conjugates, in which sequence-specific oligonucleotides serve as gene-regulatory therapeutic cargos, our AODCs use noncoding oligonucleotide-like chains as multivalent chemotherapeutic prodrug scaffolds, thereby expanding payload capacity while preserving controlled antibody conjugation and receptor-mediated targeting. Using the nucleoside analogue gemcitabine as a model payload, we synthesized structurally defined oligonucleotide-like prodrug polymers by solid-phase chemistry and engineered their backbone composition to balance metabolic stability with productive intracellular drug release. Conjugation of these architectures to antibodies targeting HER2 or CD38 generated high-capacity AODCs carrying multiple prodrug chains while maintaining antigen recognition and efficient cellular uptake, resulting in sustained tumor accumulation and enhanced intratumoral drug deposition across both solid and hematological tumor models. Importantly, intracellular release of gemcitabine from the oligonucleotide prodrug architectures induced hallmarks of immunogenic cell death, promoted dendritic-cell activation and antigen presentation, and remodeled the tumor immune microenvironment to support adaptive antitumor responses. These chemo-immunostimulatory effects translated into markedly enhanced therapeutic efficacy in combination with PD-1 blockade. Together, these results support AODCs as a programmable high-capacity payload platform that converts targeted antibody delivery into an integrated chemo-immunotherapy modality and define a generalizable strategy for expanding the chemical space of therapeutics compatible with antibody-based cancer immunotherapy.