911 Facial intradermal administration: a novel brain targeting strategy with immune-modulating cGAS-STING and STAT3 bimodal spherical nucleic acids for anti-glioma effect

Background Glioblastoma (GBM) remains one of the most challenging malignant brain tumors to treat due to its infiltrative nature, limited drug penetration across the blood-brain barrier (BBB), and immunosuppressive tumor microenvironment (TME). The median survival is about 15 months, and fewer than 5% of patients survive five years. While immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, their efficacy in GBM is hindered by an immune ‘cold’ environment characterized by abundant myeloid cells and scant T-cell infiltration. Drug delivery to the central nervous system (CNS) is complicated by the BBB, which restricts most systemically administered therapeutics. Oligonucleotide-based therapies show promise against cancer but are difficult to deliver to the CNS because unmodified oligonucleotides degrade rapidly and struggle to enter cells efficiently.Methods To address GBM’s immunosuppressive TME and poor drug penetration, we employed two strategies: (1) reprogram immune suppression using Spherical Nucleic Acids (SNAs), and (2) bypass the BBB through minimally invasive facial intradermal delivery. We developed bimodal SNAs (bi-SNAs) that concurrently activate the cGAS-STING pathway and inhibit STAT3 to shift the immune balance, reprogram myeloid cells, and enhance T-cell infiltration. Furthermore, we administered bi-SNAs via facial intradermal injection in murine GBM models, a minimally invasive strategy designed to leverage vasculature and lymphatics of the peripheral system for targeted delivery to the brain and the draining lymph nodes.Results Our in vitro and in vivo studies demonstrate that bimodal SNAs inhibit STAT3 and activate cGAS-STING signaling, offering greater therapeutic benefit than cGAS-SNAs alone in immunosuppressive, radioresistant glioma models ( figures 1 and 2). Flow cytometry showed decreased myeloid suppression and increased CD4+/CD8+ T-cell activation in the tumor, dura, and lymph nodes, indicating effective immune reprogramming. Biodistribution analyses using MRI (Gd-SNAs), 3D fluorescence CT (ICG-SNAs), and ICP-MS revealed rapid SNA trafficking from the nasal cavity to brain and lymphatic tissues, with improved targeting and reduced systemic exposure compared to intravenous or intranasal routes (figure 2). When combined with a single 8 Gy radiation dose, bi-SNAs enhanced antigen presentation, increased PD-1 expression on T cells, and suppressed tumor growth—supporting their potential to improve ICI efficacy.Conclusions Our findings show that facial intradermal delivery of bi-SNAs engages a neural-lymphatic transport network, bypasses the BBB, and achieves immune reprogramming at multiple anatomical sites relevant to GBM. This approach offers a scalable, non-invasive delivery platform for precision immunotherapy and holds translational potential for at-home administration, broadening therapeutic access for patients with brain tumors.Abstract 911 Figure 1In vitro anaylsis of bimodal SNAsAbstract 911 Figure 2Immune cell profiling and biodistribution of Bimodal SNAs post intradermal delivery