Antibody-DNA nanostructure conjugates integrate doxorubicin and rituximab to enhance therapeutic efficacy for DLBCL - Drug Advances

Sep 29, 2026

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Diffuse large B-cell lymphoma (DLBCL) remains difficult to cure for many patients because chemotherapy—especially R-CHOP—can lead to relapse, drug resistance, and substantial toxicities. Antibody-drug conjugates have advanced clinical testing, motivating DNA nanostructure–based delivery. The study constructs a rituximab–DNA tetrahedron–doxorubicin conjugate (RTD) using DNA tetrahedra for loading and coupling, validating strong in vitro anticancer activity. In a subcutaneous tumor model, RTD maintains potent efficacy while reducing doxorubicin-associated cardiotoxicity and hematotoxicity, supporting next-generation ADC development.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

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Introduction

R-CHOP limitations in DLBCL

Rationale for antibody-drug conjugates (ADCs)

DNA tetrahedra as a drug-delivery platform

DRUG ADVANCES Antibody-DNA nanostructure conjugates integrate doxorubicin andrituximab to enhance therapeutic efficacy for DLBCL Zuguang Xia, 1, 2,* Jiazhen Cao,3,* Yingzhu Li,4 Jianing Wu,4 Jun Ren,4 Weiqi Sheng,2,5,6 Chengxun Li,7 and Shengjie Li4 1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; 2 Department of Oncology, Shanghai Medical College, 3 Department of Laboratory Medicine, Huashan Hospital, and 4 Department of Clinical Laboratory, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China; 5 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; and 6 Institute of Pathology, and 7 Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China The primary clinical approach for diffuse large B-cell lymphoma (DLBCL) in recent decades has predominantly relied on chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as the cornerstone. However, given the highly heterogeneous nature of DLBCL, >30% of patients are prone to relapse and may even exhibit resistance to treatment. Antibody-drug conjugate (ADC) therapies have demonstrated significant advancements in clinical trials targeting DLBCL, thereby indicating a promising direction for its management. By leveraging the inherent modifiability of DNA nanostructures and the affinity of doxorubicin for DNA, we used a combination of rituximab-based R-CHOP scheme and DNA tetrahedra to fabricate antibody-DNA nanostructure conjugate (ADNC). Therituximab-tetrahedron-doxorubicin conjugate (RTD) studied in our research has been validated through in vitro cellular experiments and subcutaneous tumor models. The RTD demonstrated a robust antitumor effect in vitro, significantly exceeding the combined effects of rituximab and doxorubicin by >50-fold. Furthermore, confirmation from a subcutaneous tumor model substantiated the potent antitumor efficacy of RTD while successfully mitigating cardiotoxicity and hematotoxicity associated with doxorubicin. ADNC effectively facilitates the binding of rituximab and doxorubicin in the R-CHOP regimen, offering novel prospects for the development of next-generation ADC drugs. Introduction Diffuse large B-cell lymphomas (DLBCLs), accounting for ~30% of all non-Hodgkin lymphoma cases worldwide and affecting ~150 000 individuals annually, typically manifest as progressive lymphadenopathy or extranodal disease.1 Despite most patients being diagnosed at an advanced stage, >60% can achieve a cure through the administration of R-CHOP (rituximab [RTM], cyclophosphamide, doxorubicin [DOX], vincristine, and prednisone) immunochemotherapy.1 Currently, DLBCL treatment encounters 2 primary challenges: first, 40% of patients still experience relapse and exhibit poor survival outcomes after R-CHOP therapy2 ; and second, the R-CHOP–based treatment regimen using a substantial quantity of chemotherapy drugs may induce severe toxic side effects in patients.3 Therefore, the development of novel therapeutic strategies is currently an imperative. Submitted 12 May 2025; accepted 30 August 2025; prepublished online on Blood Advances First Edition 30 September 2025. [https://doi.org/10.1182/](https://doi.org/10.1182/)[ ](https://doi.org/10.1182/)[bloodadvances.2025017118](bloodadvances.2025017118.)[.](bloodadvances.2025017118.) *Z.X. and J.C. contributed equally to this work. The data generated in this study are available within the article and its supplemental Data files. The full-text version of this article contains a data supplement. © 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. 23 DECEMBER 2025 • VOLUME 9, NUMBER 24 6549 In the POLARIX phase 3 study, the addition of th

FAQs

Why is R-CHOP challenging for many DLBCL patients?

A substantial fraction of patients relapse and show poor survival after R-CHOP, and the regimen’s high chemotherapy burden can cause severe toxic side effects.

What conjugate design does the study develop?

It fabricates an antibody-DNA nanostructure conjugate by combining a rituximab-based R-CHOP component with DNA tetrahedra, then loading doxorubicin to form the RTD conjugate.

What evidence supports RTD’s improved therapeutic profile?

RTD shows robust antitumor effects in vitro, exceeding the combined effects of rituximab and doxorubicin by over 50-fold, and retains strong efficacy in a subcutaneous tumor model while mitigating doxorubicin cardiotoxicity and hematotoxicity.

Sep 29, 2026

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