Abstract 3015: Advancing mRNA therapeutics towards immuno-oncology applications: Lipid nanoparticles demonstrate favorable safety and efficacy profile with repeated mRNA administration in normal and tumor-bearing mice

Abstract Lipid nanoparticles (LNPs) have revolutionized mRNA delivery, offering a promising approach for advancing cancer immunotherapy. Effective and safe delivery of tumor antigen-encoding mRNA can stimulate robust anti-tumor immune responses. Here, we developed LNP formulations for immuno-oncology applications and tested its fit-for-use by delivering ovalbumin (OVA)-encoded mRNA as a surrogate payload and evaluated the safety, efficacy, and therapeutic potential in the B16-F10-OVA xenograft melanoma mouse model. Novel ionizable lipids were selected for formulating LNPs by rational screening of pKa, encapsulation efficiency, hydrodynamic size, and biodistribution properties. OVA-encoded mRNA was encapsulated in LNPs using NxGen™ microfluidic mixing technology on the NanoAssemblr™ platform. The LNPs were characterized for hydrodynamic size, polydispersity index (PDI), loading, and encapsulation efficiency. To assess long-term safety and stability, healthy mice received multiple intramuscular (IM) injections of the LNP formulations at 21-day intervals. Physicochemical stability and toxicity were evaluated through the standard assays and clinical observations. Following this series, B16-F10-OVA tumor-bearing mice were vaccinated intramuscularly with OVA mRNA-loaded LNPs. Clinical symptoms and survival outcomes were monitored and compared to untreated controls. OVA mRNA-loaded LNPs were in the desired size range of 60 to 80 nm with a PDI value below 0.2 and an encapsulation efficiency greater than 95%. Long-term stability studies indicated retention of critical quality attributes (CQAs). Repeated IM administration of the proprietary LNPs over an extended period demonstrated stability and tolerability with no detectable toxicity or adverse effects observed in treated animals. Treatment with the OVA mRNA-LNP vaccine improved survival in tumor-bearing mice, significantly extending median survival compared to controls. By retaining the CQAs of the drug products, our novel LNP platform efficiently delivers OVA mRNA as a model for delivering therapeutic or immune modulating nucleic acid payloads. Additionally, repeated IM administrations of these LNPs over an extended period resulted in no detectable adverse events and OVA mRNA LNPs induced potent anti-tumor effects in the B16-F10-OVA model. This favorable safety profile and stability upon repeated dosing underscore LNP suitability for long-term immune modulation or therapeutic strategies for immuno-oncology applications. Citation Format: Sams MA Sadat, Avisek Deyati, Leanna Yee, Zhengyu Chen, Kalyan Golla, Tony Wu, Richard Jiang, Jay Paquette, Malathi Anantha, Noorjahan Aibani, Nikita Jain, Anitha Thomas. Advancing mRNA therapeutics towards immuno-oncology applications: Lipid nanoparticles demonstrate favorable safety and efficacy profile with repeated mRNA administration in normal and tumor-bearing mice 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 3015.