KRAS mRNA Spleen-Targeting Lipid Nanoparticles Synergize with Irinotecan Silicasomes to Robustly Augment the Cancer Immunity Cycle in Pancreatic Cancer

Fig 1. Schematic to explain a dual nanocarrier strategy for enhancing PDAC Tumor Immunity. The schematic illustrates a dual vaccination strategy, hypothesized to enhance the PDAC tumor immunity cycle by integrating endogenous and exogenous vaccination approaches. This strategy employs two distinct nanocarriers to synergistically reinforce CTL activation against PDAC. Endogenous Vaccination: Chemotherapeutic agents such as irinotecan induce ICD, triggering the release of tumor antigens and DAMPs, including HMGB1, ATP, and CRT. These signals promote the uptake of endogenous tumor antigens and activation of APC, which in turn prime CTLs. The proposed use of silicasome-encapsulated irinotecan - incorporating the TLR7/8 agonist 3M-052 - further enhances APC activation and antigen presentation, thereby strengthening the immune response. Exogenous Vaccination: In parallel, spleen-targeting LNPs delivering mutant KRAS mRNA and a TLR7/8 agonist are proposed to augment the immune response by increasing the frequency of CTLs within the spleen. These activated tumor-specific CTLs subsequently migrate to the primary tumor site, where they mediate effective cancer cell killing. By integrating these two vaccination mechanisms, the strategy aims to optimize the cancer immunity cycle, leading to a more robust and sustained anti-tumor immune response.

Authors: Lijia Luo, Xiang Wang, Yu-Pei Liao, Andre E. Nel

Affiliation: Department of Medicine, University of California, Los Angeles

Introduction

This research falls under cancer immunotherapy and nanomedicine, specifically the emerging application of lipid nanoparticles (LNPs) to this longstanding field. Pancreatic cancer remains one of the most aggressive and treatment-resistant malignancies due to its immunosuppressive properties, though additional exogenous targeting of the spleen is hypothesized to help. Targeted mRNA delivery to the spleen may be accomplished with LNPs, so a dual-treatment approach must integrate cutting-edge nanotechnology with established chemotherapeutic agents.

Materials and Methods

Luo and colleagues employed a sophisticated approach utilizing LNPs specifically engineered to target KRAS mRNA to the spleen through a novel delivery system. The LNPs were prepared using the PreciGenome NanoGenerator Flex-M Instrument, which provides precise control over flow rate conditions and therefore particle attributes like size, uniformity, and zeta potential.

The experimental framework combined these spleen-targeting LNPs with irinotecan silicasomes to evaluate their synergistic effects on the cancer immunity cycle in pancreatic cancer models. The LNPs incorporated G12D KRAS mutant mRNA with a STING agonist to prevent metastatic cancer spread, while the silicasomes delivered irinotecan directly to the tumors to induce immunogenic cell death. Performance was evaluated with a murine model subjected to intravenous injection of LNPs.

Results

The experimental results demonstrated robust augmentation of the cancer immunity cycle, with significant tumor regression observed in treated pancreatic cancer models. The combination therapy showed high target specificity, with both LNPs and silicasomes demonstrating localized distribution based on their target organ. Additionally, the treatment enhanced immune cell infiltration and activation, leading to substantially improved therapeutic outcomes compared to monotherapies. These findings suggest that the synergistic approach not only delivers targeted therapeutic molecules more effectively, but also amplifies the body's natural immune response against cancer cells.

Fig 2. Combination of 3M-LNP/mKRASG12D with 3M-Si-IR prolong survival in orthotopic tumors. (A) Experimental outline of the study conducted in an orthotopic KPC tumor model, looking at the survival impact of triggering the endogenous ICD pathway before administration of the exogenous LNP vaccine. (B) IVIS imaging was performed at multiple time points. (C) Quantification of tumor bioluminescence intensity for each group on days 10, 15, 19, and 26. Significant tumor reduction was observed with combination therapy. (D) Kaplan–Meier plots to display the different animal groups' survival rates, MST, and %ILS. Data represents mean ± SEM. #p < 0.05; ###p < 0.001; p < 0.05; *p < 0.01.

These key findings center on three major achievements: successful spleen-targeting delivery of KRAS mRNA with LNPs, the demonstrated synergistic effect between mRNA-LNPs and irinotecan silicasomes, and the overall enhancement of the cancer immunity cycle. This combination represents a promising therapeutic strategy that could potentially transform pancreatic cancer treatment approaches.

Conclusion

This research makes a significant contribution to the field of cancer immunotherapy by demonstrating a viable combination therapy with high target specificity. Targeted nanoparticle systems can be engineered to enhance natural immune responses while simultaneously delivering therapeutic agents. Further integration with chemotherapy represents an even more potent therapeutic paradigm that could influence future treatment protocols.

The study's demanding specificity requirements rely heavily on tunable and controlled preparation conditions for LNPs. The NanoGenerator Flex-M used by the authors allows accurate flow rate control during LNP synthesis, ensuring reliable microfluidic mixing.

For further reading: https://advanced.onlinelibrary.wiley.com/doi/full/10.1002/advs.202504886