A Rationally Engineered Spleen-Tropic One-Component Lipid-mRNA Complex (OncoLRC) for Cancer Vaccines

Area of Science:

• Biotechnology
• Immunology
• Nanomedicine

Background:

• mRNA vaccines hold promise for cancer immunotherapy but face challenges in delivering mRNA to antigen-presenting cells (APCs) in lymphoid organs.
• Efficient and targeted delivery of mRNA to APCs is crucial for effective cancer vaccine development.

Purpose of the Study:

• To introduce OncoLRC, a novel one-component lipid-mRNA complex engineered for spleen-targeting mRNA delivery to APCs.
• To evaluate the efficacy of OncoLRC as a platform for mRNA cancer vaccines.

Main Methods:

• Systemic screening and optimization of a dimethylamino (DMA)-lipidoid-based formulation for spleen-targeting mRNA delivery.
• Formulation of OncoLRC with ovalbumin (OVA) mRNA (OncoLRC^OVA) and assessment of its effects on dendritic cell (DC) maturation and activation.
• Evaluation of OncoLRC^OVA in a B16F10-OVA tumor model, including combination therapy with immune checkpoint blockade.

Main Results:

• OncoLRC achieved nearly exclusive spleen-targeting mRNA delivery, outperforming conventional lipid nanoparticles (LNPs) with a reduced lipid-to-mRNA ratio.
• OncoLRC^OVA promoted DC maturation, elicited robust antigen-specific immune responses, and enhanced IL-12 secretion.
• OncoLRC^OVA demonstrated prophylactic antitumor efficacy and synergistic effects with immune checkpoint blockade in a cold tumor model.

Conclusions:

• OncoLRC is a simple, effective, and spleen-tropic mRNA delivery platform for APC targeting.
• OncoLRC represents a promising next-generation system for mRNA cancer vaccines.
• Targeted delivery via OncoLRC enhances immune responses and antitumor efficacy.