B Cell Engineering via Spherical Nucleic Acids for Cancer Immunotherapy

Adoptive cellular therapy (ACT) has revolutionized cancer immunotherapy, yet its focus remains largely on T cells. B cells, despite their potent antigen-presenting capacity and role in adaptive immunity, have been underutilized due to inefficient antigen delivery and activation. We developed an ex vivo strategy leveraging spherical nucleic acids (SNAs) to license B cells for ACT. This platform synchronizes pH-controlled co-delivery of tumor antigen peptides and TLR9 agonists into shared endosomal compartments, enabling sustained antigen presentation and robust cross-priming of tumor-specific CD8+ T cells, resulting in epitope spreading and durable antitumor immunity. SNA-trained B cells exhibited lymphoid homing and secreted CCL3/CCL4, establishing a CCR5-dependent chemotactic axis that recruited effector CD8+ T cells and cDC1, creating spatial immune hubs within tumors. Multiplex immunohistochemistry analysis revealed clustering of transferred B cells, CD8+ T cells, and cDC1 in draining lymph nodes, facilitating antigen handoff and reciprocal activation. Mechanistic studies confirmed that CCR5 blockade or CD8+ T-cell depletion abrogated efficacy. Across multiple murine and humanized tumor models, SNA-trained B cells outperformed controls, reduced metastasis, and synergized with PD-1 blockade to improve survival. Single-cell transcriptomics and BCR-seq demonstrated progression toward plasma cell differentiation, oligoclonal expansion, and IgG2 class switching.This work introduces a nanomaterial-based platform to reprogram B cells for ACT, overcoming limitations in immunologically “cold” and checkpoint-refractory tumors. SNA-trained B cells broaden the ACT paradigm beyond T cells, offering a versatile and well-tolerated strategy for durable antitumor immunity. Citation Format: Maryam Balibegloo, Yingying Li, Abu Baker, Jie Fan, Ping Xie, Mi Ran Choi, Catalina Lee Chang, Vinzenz Mayer, Michael Evangelopoulos, Chad A. Mirkin, Bin Zhang. Expanding the ACT paradigm: B cell engineering via spherical nucleic acids for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 130.