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

Abstract 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). The rituximab-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.