Synergistic co-delivery approaches for next-generation mRNA cancer immunotherapy

The advent of messenger RNA (mRNA) vaccines as a novel platform in immunotherapy has been made possible by their ability to be rapidly produced, flexibly designed, and induce humoral and cellular immunity. However, their broader applicability is limited by challenges in delivery efficiency, immune modulation, and disease-specific targeting. To address this, co-delivery strategies have also been developed to enable synergistic effects by combining mRNA with other bioactive compounds, including immune adjuvants (e.g., Toll-like receptor [TLR] or stimulator of interferon genes [STING] agonists), cytokines (e.g., granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin-12 [IL-12]), RNA interference molecules (e.g., small interfering RNA targeting PD-L1 [siPD-L1], microRNA-155 [miR-155]), and small-molecule drugs (e.g., chemotherapeutics, checkpoint inhibitors). All these approaches enhance antigen presentation, reshape the immunosuppressive tumor microenvironment, and establish potent adaptive immunity. This article provides a systematic review of recent advances in mRNA co-delivery systems, focusing on carrier biology, immunobiological outcomes, and clinical development, with particular emphasis on disease-specific customization and translational challenges. By integrating co-delivery concepts with precision immunotherapy, mRNA vaccines hold promise as next-generation platforms against cancer, chronic infections, and viral threats. To provide a clear conceptual framework, we outline four main co-delivery strategies: co-administration of immune adjuvants, cytokines, RNA interference tools, and small-molecule therapeutics, each addressing distinct barriers to vaccine effectiveness.