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Although conventional linkers generally provide systemic stability, recent studies indicate that retention of intact antibody\u2010guided conjugates in normal tissues can cause chronic toxicity. Here, we report an antibody\u2010guided delivery platform leveraging the pH\u2010responsive properties of i\u2010motif functional nucleic acids (iM) for targeted chemo\u2010 and radiotherapy. Using trastuzumab as the targeting moiety, the platform (Tra\u2010iM) achieves selective payload delivery. Within the acidic tumor microenvironment, the i\u2010motif forms a stable quadruplex, promoting effective payload accumulation in tumor lesions. Under physiological conditions, nuclease\u2010sensitive linear i\u2010motif structures trigger rapid disassembly of Tra\u2010iM, generating hydrophilic nucleic acid fragments that minimize off\u2010target penetration and facilitate clearance of hydrophobic payloads. Fluorescence and PET imaging showed reduced normal\u2010organ retention and faster clearance of the labeled payload\u2010bearing components. Therapeutic evaluations demonstrate that Tra\u2010iM preserves targeted delivery and efficacy while markedly reducing hematologic and hepatic toxicity after high\u2010dose administration. This strategy significantly enhances the biosafety of antibody\u2010guided therapeutics and highlights the potential of metabolite\u2010regulated delivery platforms to advance targeted nanomedicine.<\/jats:p>","DOI":"10.1002\/smll.76106","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:14:14Z","timestamp":1791551654000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Nucleic Acid\u2010Antibody Conjugates for Effective Tumor Targeted Therapy With Controllable Side Effects"],"prefix":"10.1002","author":[{"given":"Jia","family":"Liu","sequence":"first","affiliation":[{"name":"Institute of Molecular Medicine (IMM) Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine Renji Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 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