Functional Nucleic Acid‐Antibody Conjugates for Effective Tumor Targeted Therapy With Controllable Side Effects

Antibody-guided therapeutics, including antibody-drug conjugates and radiopharmaceuticals, efficiently deliver payloads to tumor lesions, but the weeks-long half-life of antibodies promotes accumulation in normal tissues, increasing the risk of off-target toxicity. Although conventional linkers generally provide systemic stability, recent studies indicate that retention of intact antibody-guided conjugates in normal tissues can cause chronic toxicity. Here, we report an antibody-guided delivery platform leveraging the pH-responsive properties of i-motif functional nucleic acids (iM) for targeted chemo- and radiotherapy. Using trastuzumab as the targeting moiety, the platform (Tra-iM) achieves selective payload delivery. Within the acidic tumor microenvironment, the i-motif forms a stable quadruplex, promoting effective payload accumulation in tumor lesions. Under physiological conditions, nuclease-sensitive linear i-motif structures trigger rapid disassembly of Tra-iM, generating hydrophilic nucleic acid fragments that minimize off-target penetration and facilitate clearance of hydrophobic payloads. Fluorescence and PET imaging showed reduced normal-organ retention and faster clearance of the labeled payload-bearing components. Therapeutic evaluations demonstrate that Tra-iM preserves targeted delivery and efficacy while markedly reducing hematologic and hepatic toxicity after high-dose administration. This strategy significantly enhances the biosafety of antibody-guided therapeutics and highlights the potential of metabolite-regulated delivery platforms to advance targeted nanomedicine.