Abstract A027: Harnessing facial neuronal-lymphatic pathways for face-to-brain delivery of bimodal cGAS-STAT3 Spherical Nucleic Acids for anti-glioma therapy

Abstract Background: Central nervous system (CNS) border pathways, including meningeal lymphatics, trigeminal neurovascular networks, and cribriform plate conduits, are increasingly recognized as routes for immune surveillance and therapeutic access to the brain. However, strategies to actively enhance trafficking through these interfaces remain limited, particularly for nanotherapeutic delivery in glioblastoma (GBM). Here, we developed facial dermal based system to deliver immune-modulating nanoparticles through the neuro-lymphatic network. Methods: To overcome physical barriers limiting immunotherapeutic access to CNS and peripheral immune sites, we implemented two mechanistically integrated strategies. First, we established facial intradermal (i.d.) delivery combined with iontophoresis as a minimally invasive approach to enhance CNS trafficking across the brain border interfaces. Iontophoresis utilizes low-intensity electric fields to promote directional transport of charged therapeutics into deeper tissues. Second, we engineered charged nanotherapeutic particles bimodal Spherical Nucleic Acid (bi-SNA) platform designed to leverage electric field-guided transport from the face to the CNS borders while activating cGAS–STING and inhibiting STAT3. This bi-SNA consists of a 15-nm gold core functionalized with a hairpin oligonucleotide containing an unpaired G5 repeat loop flanked by STAT3-decoy palindromic sequences, enabling simultaneous cGAS activation and cytosolic sequestration of STAT3. Results: Iontophoresis-augmented i.d. delivery achieved significantly enhanced nanoparticle trafficking across CNS border pathways compared with i.d administration. IVIS/CT imaging of fluorescent probe-tagged SNA in mouse whole-head demonstrated robust SNA flux from facial injection sites to intracranial compartments, with transport occurring along maxillary–olfactory and temporomandibular–trigeminal neuro-lymphatic routes. I.d. delivery also resulted in accumulation within superficial lymph nodes, indicating engagement of peripheral immune compartments. ICP-MS gold element quantification revealed ∼20-fold higher gold accumulation in the brain and trigeminal nerve and lymph nodes within 12 hours following iontophoresis-assisted i.d delivery compared with passive i.d. (p<0.01). Silver staining of mouse brain histology sections confirmed SNA localization within the meninges, trigeminal nerve branches, maxillary sinus, and cortex. Furthermore, flow cytometry revealed decreased immunosuppressive myeloid populations and increased CD4+ and CD8+ T-cell activation across tumor, dura, and deep cervical lymph nodes. In combination with radiation, bi-SNA facial i.d. treatment significantly reduced tumor burden, enhanced antigen presentation in tumor microglia and myeloid cells, and increased PD-1 expression on T cells, supporting the potential of checkpoint inhibitor combinations. Conclusions: Iontophoresis-assisted facial intradermal delivery enables non-vascular CNS entry of bi-SNA nanotherapeutics by exploiting craniofacial neuronal and lymphatic brain border pathways. Citation Format: Akanksha S. Mahajan, Davin Hickman. Chow, Gaelen Clayton, Seunghyun Kim, Rachel Jarvis, Emma Shen, Clara Foltz, Cao Dai Phung, Eric Leuthardt, Alexander Stegh. Harnessing facial neuronal-lymphatic pathways for face-to-brain delivery of bimodal cGAS-STAT3 Spherical Nucleic Acids for anti-glioma therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A027.