Fast tumor accumulation and payload release of c-Met targeting aptamer-drug conjugate enables robust anti-tumor efficacy.

c-Met overexpression promotes tumor progression in many cancers, yet approved inhibitors benefit only patients with MET mutation, leaving most c-Met-overexpressing patients without effective therapy. Inspired by antibody-drug conjugates (ADCs), composed of an antibody linked to cytotoxic agents, a c-Met-targeting drug conjugate enabling MET-independent cytotoxicity offers a strategy to address this gap. Here, we developed an aptamer-drug conjugate (ApDC), integrating SL1, a c-Met-targeting aptamer-short oligonucleotide with high target affinity-with monomethyl auristatin E (MMAE), via cathepsin B-sensitive linker. This ApDC selectively binds c-Met-overexpressing cells, undergoes receptor-mediated internalization, and releases MMAE to induce apoptosis. It achieves efficient tumor accumulation, sustained payload retention, rapid systemic clearance, and robust anti-tumor efficacy across multiple c-Met overexpressing tumor models. With maintained surface receptor expression, rapid tumor accumulation and active payload release, it outperforms a benchmark c-Met-targeting ADC. Combining precise targeting, potent efficacy and favorable safety, this ApDC represents a promising strategy for c-Met-targeted cancer therapy.