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DNA–drug conjugates enable logic-gated drug delivery amplified by hybridization chain reactions

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  • Beck, A., Goetsch, L., Dumontet, C. & Corvaïa, N. Strategies and challenges for the next generation of antibody drug conjugates. Nat. Rev. Drug Discov. 16, 315–337 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Fu, Z. W., Li, S. J., Han, S. F., Shi, C. & Zhang, Y. Antibody drug conjugate: the ‘biological missile’ for targeted cancer therapy. Signal Transduct. Tar. 7, 93 (2022).

  • Dumontet, C., Reichert, J. M., Senter, P. D., Lambert, J. M. & Beck, A. Antibody-drug conjugates come of age in oncology. Nat. Rev. Drug Discov. 22, 641–661 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Tsuchikama, K., Anami, Y., Ha, S. Y. Y. & Yamazaki, C. M. Exploring the next generation of antibody-drug conjugates. Nat. Rev. Clin. Oncol. 21, 203–223 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Xu, S. Internalization, trafficking, intracellular processing and actions of antibody-drug conjugates. Pharm. Res. 32, 3577–3583 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bordeau, B. M., Yang, Y. J. & Balthasar, J. P. Transient competitive inhibition bypasses the binding site barrier to improve tumor penetration of trastuzumab and enhance T-DM1 efficacy. Cancer Res. 81, 4145–4154 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Rubahamya, B., Dong, S. & Thurber, G. M. Clinical translation of antibody drug conjugate dosing in solid tumors from preclinical mouse data. Sci. Adv. 10, 1894 (2024).

    Article 

    Google Scholar 

  • Gebauer, M. & Skerra, A. Engineered protein scaffolds as next-generation antibody therapeutics. Curr. Opin. Chem. Biol. 13, 245–255 (2009).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Löfblom, J. et al. Affibody molecules: engineered proteins for therapeutic, diagnostic and biotechnological applications. FEBS Lett. 584, 2670–2680 (2010).

    Article 
    PubMed 

    Google Scholar 

  • Ståhl, S. et al. Affibody molecules in biotechnological and medical applications. Trends Biotechnol. 35, 691–712 (2017).

    Article 
    PubMed 

    Google Scholar 

  • Orlova, A. et al. Tumor Imaging using a picomolar affinity HER2 binding affibody molecule. Cancer Res. 66, 4339–4348 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Feldwisch, J. et al. Design of an optimized scaffold for affibody molecules. J. Mol. Biol. 398, 232–247 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Andersson, K. G. et al. Feasibility of imaging of epidermal growth factor receptor expression with ZEGFR:2377 affibody molecule labeled with Tc using a peptide-based cysteine-containing chelator. Int. J. Oncol. 49, 2285–2293 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Da Pieve, C. et al. Efficient radiolabeling of Z affibody molecule for imaging of HER3 positive tumors. Bioconj. Chem. 27, 1839–1849 (2016).

    Article 

    Google Scholar 

  • Han, J. Y. et al. Therapeutic efficacy and imaging assessment of the HER2-targeting chemotherapy drug Z-pemetrexed in lung adenocarcinoma xenografts. Invest. New Drug 38, 1031–1043 (2020).

    Article 
    CAS 

    Google Scholar 

  • Alhuseinalkhudhur, A. et al. Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer. EJNMMI Res. 10, 21 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Liang, Z. G., Hu, X. W., Hu, H. Y., Wang, P. & Cai, J. Novel small 99-Tc-labeled affibody molecular probe for PD-L1 receptor imaging. Front. Oncol. 12, 1017737 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • de Souza, A. L. R. et al. Fluorescent affibody molecule administered at a microdose level labels EGFR expressing glioma tumor regions. Mol. Imaging Biol. 19, 41–48 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Serwotka-Suszczak, A. M. et al. A conjugate based on Anti-HER2 diaffibody and auristatin E targets HER2-positive cancer cells. Int. J. Mol. Sci. 19, 3676 (2018).

  • Tsurutani, J. et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, Phase I study in multiple advanced solid tumors. Cancer Discov. 10, 688–701 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. New Engl. J. Med. 382, 610–621 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Shitara, K. et al. Discovery and development of trastuzumab deruxtecan and safety management for patients with HER2-positive gastric cancer. Gastric Cancer 24, 780–789 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Yin, P., Choi, H. M. T., Calvert, C. R. & Pierce, N. A. Programming biomolecular self-assembly pathways. Nature 451, 318–322 (2008).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Qian, L. & Winfree, E. Scaling up digital circuit computation with DNA strand displacement cascades. Science 332, 1196–1201 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Zhang, D. Y. & Seelig, G. Dynamic DNA nanotechnology using strand-displacement reactions. Nat. Chem. 3, 103–113 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Dirks, R. M. & Pierce, N. A. Triggered amplification by hybridization chain reaction. Proc. Natl Acad. Sci. USA 101, 15275–15278 (2004).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Jung, C. & Ellington, A. D. Diagnostic applications of nucleic acid circuits. Acc. Chem. Res. 47, 1825–1835 (2014).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Koos, B. et al. Proximity-dependent initiation of hybridization chain reaction. Nat. Commun. 6, 7294 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zhao, Y. X., Chen, F., Li, Q., Wang, L. H. & Fan, C. H. Isothermal amplification of nucleic acids. Chem. Rev. 115, 12491–12545 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Li, J., Green, A. A., Yan, H. & Fan, C. H. Engineering nucleic acid structures for programmable molecular circuitry and intracellular biocomputation. Nat. Chem. 9, 1056–1067 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Chang, X. et al. Construction of a multiple-aptamer-based DNA logic device on live cell membranes via associative toehold activation for accurate cancer cell identification. J. Am. Chem. Soc. 141, 12738–12743 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Zhang, C. et al. Cancer diagnosis with DNA molecular computation. Nat. Nanotechnol. 15, 709–715 (2020).

    Article 
    PubMed 

    Google Scholar 

  • Benenson, Y., Gil, B., Ben-Dor, U., Adar, R. & Shapiro, E. An autonomous molecular computer for logical control of gene expression. Nature 429, 423–429 (2004).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Douglas, S. M., Bachelet, I. & Church, G. M. A logic-gated nanorobot for targeted transport of molecular payloads. Science 335, 831–834 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Kim, K. T., Angerani, S., Chang, D. L. & Winssinger, N. Coupling of DNA circuit and templated reactions for quadratic amplification and release of functional molecules. J. Am. Chem. Soc. 141, 16288–16295 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Emanuelson, C., Bardhan, A. & Deiters, A. DNA logic gates for small molecule activation circuits in cells. ACS Synth. Biol. 13, 538–545 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Prinzen, A. L. et al. Amplified self-immolative release of small molecules by spatial isolation of reactive groups on DNA-minimal architectures. Angew. Chem. Int. Ed. 59, 12900–12908 (2020).

    Article 
    CAS 

    Google Scholar 

  • Wang, D., Li, S. H., Zhao, Z. L., Zhang, X. B. & Tan, W. H. Engineering a second-order DNA logic-gated nanorobot to sense and release on live cell membranes for multiplexed diagnosis and synergistic therapy. Angew. Chem. Int. Ed. 60, 15816–15820 (2021).

    Article 
    CAS 

    Google Scholar 

  • Li, S. P. et al. A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger. Nat. Biotechnol. 36, 258–264 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Dockerill, M. et al. Development of supramolecular anticoagulants with on-demand reversibility. Nat. Biotechnol. 43, 186–193 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Yu, H. X. et al. Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors. Nat. Commun. 15, 3977 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Tolmachev, V. et al. Imaging of EGFR expression in murine xenografts using site-specifically labelled anti-EGFR In-DOTA-Z Affibody molecule: aspect of the injected tracer amount. Eur. J. Nucl. Med. Mol. I. 37, 613–622 (2010).

    Article 

    Google Scholar 

  • Ang, Y. S., Qiu, X. Z., Yam, H. M., Wu, N. J. & Yung, L. Y. L. Enzyme-free and isothermal discrimination of microRNA point mutations using a DNA split proximity circuit with turn-on fluorescence readout. Biosens. Bioelectron. 217, 114727 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • He, A. X. et al. Structure- based investigation of a DNA aptamer targeting PTK7 reveals an intricate 3D fold guiding functional optimization. Proc. Natl Acad. Sci. USA 121, E2404060121 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Shangguan, D. et al. Aptamers evolved from live cells as effective molecular probes for cancer study. Proc. Natl Acad. Sci. USA 103, 11838–11843 (2006).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Doronina, S. O. et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat. Biotechnol. 21, 778–784 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Li, W. et al. Synthesis and evaluation of camptothecin antibody-drug conjugates. ACS Med. Chem. Lett. 10, 1386–1392 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Melkko, S., Dumelin, C. E., Scheuermann, J. & Neri, D. On the magnitude of the chelate effect for the recognition of proteins by pharmacophores scaffolded by self-assembling oligonucleotides. Chem. Biol. 13, 225–231 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Ranallo, S., Prévost-Tremblay, C., Idili, A., Vallée-Bélisle, A. & Ricci, F. Antibody-powered nucleic acid release using a DNA-based nanomachine. Nat. Commun. 8, 15150 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Kato, K. et al. Model for the complex between protein-G and an antibody Fc fragment in solution. Structure 3, 79–85 (1995).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Dannenfelser, R. et al. Discriminatory power of combinatorial antigen recognition in cancer T cell therapies. Cell Syst. 11, 215–228 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Maruani, A. et al. A plug-and-play approach to antibody-based therapeutics a chemoselective dual click strategy. Nat. Commun. 6, 6645 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Strop, P. et al. Site-specific conjugation improves therapeutic index of antibody drug conjugates with high drug loading. Nat. Biotechnol. 33, 694–696 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Levengood, M. R. et al. Orthogonal cysteine protection enables homogeneous multi-drug antibody-drug conjugates. Angew. Chem. Int. Ed. 56, 733–737 (2017).

    Article 
    CAS 

    Google Scholar 

  • Kumar, A. et al. Synthesis of a heterotrifunctional linker for the site-specific preparation of antibody-drug conjugates with two distinct warheads. Bioorg. Med. Chem. Lett. 28, 3617–3621 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Yamazaki, C. M. et al. Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance. Nat. Commun. 12, 3528 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Journeaux, T. & Bernardes, G. J. L. Homogeneous multi-payload antibody-drug conjugates. Nat. Chem. 16, 854–870 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Liu, B. et al. Antibody–bottlebrush conjugates unlock diverse payloads for targeted cancer therapy. Nat. Biotechnol. https://doi.org/10.1038/s41587-025-02772-z (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Andreev, J. et al. Bispecific antibodies and antibody-drug conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Mol. Cancer Ther. 16, 681–693 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Dong, Y. J. et al. Novel bispecific antibody-drug conjugate targeting PD-L1 and B7-H3 enhances antitumor efficacy and promotes immune-mediated antitumor responses. J. Immunother. Cancer 12, e009710 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ma, Y. X. et al. BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody- drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study. Lancet Oncol. 25, 901–911 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Liu, Y. S. et al. Glycoproteomic analysis of prostate cancer tissues by SWATH mass spectrometry discovers N-acylethanolamine acid amidase and Protein Tyrosine Kinase 7 as signatures for tumor aggressiveness. Mol. Cell. Proteomics 13, 1753–1768 (2014).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Maitland, M. L. et al. First-in-human study of PF-06647020 (cofetuzumab pelidotin), an antibody-drug conjugate targeting Protein Tyrosine Kinase 7, in advanced solid tumors. Clin. Cancer Res. 27, 4511–4520 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Dessaux, C., Ganier, L., Guiraud, L. & Borg, J. P. Recent insights into the therapeutic strategies targeting the pseudokinase PTK7 in cancer. Oncogene 43, 1973–1984 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Oostindie, S. C. et al. Logic-gated antibody pairs that selectively act on cells co-expressing two antigens. Nat. Biotechnol. 40, 1509–1519 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Pedram, K. et al. Design of a mucin-selective protease for targeted degradation of cancer-associated mucins. Nat. Biotechnol. 42, 597–607 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gunnoo, S. B. et al. Creation of a gated antibody as a conditionally functional synthetic protein. Nat. Commun. 5, 4388 (2014).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Lajoie, M. J. et al. Designed protein logic to target cells with precise combinations of surface antigens. Science 369, 1637–1643 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Kofoed, C. et al. Programmable protein ligation on cell surfaces. Nature 645, 793–800 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Dovgan, I. et al. On the use of DNA as a linker in antibody-drug conjugates: synthesis, stability and potency. Sci. Rep. 10, 7691 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Mrcher, A., Nijenhuis, M. A. D. & Gothelf, K. V. A wireframe DNA cube: antibody conjugate for targeted delivery of multiple copies of monomethyl auristatin E. Angew. Chem. Int. Ed. 60, 21691–21696 (2021).

    Article 

    Google Scholar 

  • Urata, H., Shinohara, K., Ogura, E., Ueda, Y. & Akagi, M. Mirror-image DNA. J. Am. Chem. Soc. 113, 8174–8175 (1991).

    Article 
    CAS 

    Google Scholar 

  • Damha, M. J., Giannaris, P. A. & Marfey, P. Antisense L/D-oligodeoxynucleotide chimeras—nuclease stability, base-pairing properties, and activity at directing ribonuclease-H. Biochemistry 33, 7877–7885 (1994).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Schaudy, E., Somoza, M. M. & Lietard, J. l-DNA duplex formation as a bioorthogonal information channel in nucleic acid-based surface patterning. Chem. Eur. J. 26, 14310–14314 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Shearer, V., Yu, C. H., Han, X. & Sczepanski, J. T. The clinical potential of L-oligonucleotides: challenges and opportunities. Chem. Sci. 15, 18239–18258 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zhou, L. J. et al. Self-assembled L-DNA linkers for rapid construction of multi-specific antibody-drug conjugates library. Angew. Chem. Int. Ed. 62, e202302805 (2023).

    Article 
    CAS 

    Google Scholar 

  • Kazane, S. A. et al. Self-assembled antibody multimers through peptide nucleic acid conjugation. J. Am. Chem. Soc. 135, 340–346 (2013).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Shangguan, D. H., Cao, Z. H. C., Li, Y. & Tan, W. H. Aptamers evolved from cultured cancer cells reveal molecular differences of cancer cells in patient samples. Clin. Chem. 53, 1153–1155 (2007).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Kratschmer, C. & Levy, M. Effect of chemical modifications on aptamer stability in serum. Nucleic Acid Ther. 27, 335–344 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Han, Y. Q. et al. Molecular programming design of glyconucleic acid aptamer with high stability. Adv. Sci. 12, 2408168 (2024).

    Article 

    Google Scholar 

  • Zhang, Q. et al. Aptamer-based nongenetic reprogramming of CARs enables flexible modulation of T cell-mediated tumor immunotherapy. ACS Cent. Sci. 10, 813–822 (2024).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Skaanning, M. K. et al. Self-assembly of ultrasmall 3D architectures of (L)-acyclic threoninol nucleic acids with high thermal and serum stability. J. Am. Chem. Soc. 146, 20141–20146 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Chalker, J. M., Bernardes, G. J. L., Lin, Y. A. & Davis, B. G. Chemical modification of proteins at cysteine: opportunities in chemistry and biology. Chem. Asian J. 4, 630–640 (2009).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bernardim, B. et al. Stoichiometric and irreversible cysteine-selective protein modification using carbonylacrylic reagents. Nat. Commun. 7, 13128 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Walsh, S. J. et al. Site-selective modification strategies in antibody-drug conjugates. Chem. Soc. Rev. 50, 1305–1353 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Ochtrop, P. et al. Compact hydrophilic electrophiles enable highly efficacious high DAR ADCs with excellent PK profile. Chem. Sci. 14, 2259–2266 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Honarvar, H. et al. Feasibility of affibody molecule-based PNA-mediated radionuclide pretargeting of malignant tumors. Theranostics 6, 93–103 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Oroujeni, M. et al. Affibody-mediated PNA-based pretargeted cotreatment improves survival of trastuzumab-treated mice bearing HER2-expressing xenografts. J. Nucl. Med. 63, 1046–1051 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Yan, J. X. et al. Radionuclide therapy of bevacizumab-based PNA-mediated pretargeting. Nucl. Med. Commun. 45, 901–909 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Chen, S.-K. et al. DNA-drug conjugates (DDCs) for computed delivery. Zenodo https://doi.org/10.5281/zenodo.17293902 (2026).

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