Polymer-lipid hybrid nanoparticle enhances mRNA delivery and T cell-mediated immunity

Cai, X.; Chen, M.; Cao, G.; Asby, N.; Elli, D.; Gula, H.; Nicolaescu, V.; Nguyen, D.-T.; Huang, X.; Dangi, T.; Solanki, A.; Woessner, S.; Zhang, W.; Tang, E.; Volpatti, L.; Wallace, R.; Pan, T.; Nguyen, M.; Chen, Q.; Geng, Z.; Sagar, R.; Esser-Khan, A.; Penaloza-MacMaster, P.; Missiakas, D.; Huang, J.

doi:10.64898/2026.01.22.701138

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bioRxiv · 10.64898/2026.01.22.701138

Polymer-lipid hybrid nanoparticle enhances mRNA delivery and T cell-mediated immunity

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Abstract

mRNA vaccines have transformed prophylactic immunization against infectious diseases as well as therapeutic interventions for cancer. However, their effectiveness against emerging viral variants and a range of malignancies continues to be hindered by suboptimal induction of T cell-mediated immunity. To overcome this limitation, here we developed a polymer-lipid hybrid nanoparticle (PLNP) platform engineered to improve mRNA delivery to antigen-presenting cells (APCs) and to potentiate T cell responses. Relative to conventional mRNA lipid nanoparticle (LNP) vaccines, mRNA PLNP vaccines demonstrated markedly improved lymph node targeting, APC activation, Th1-biased pro-inflammatory cytokine response, and antigen-specific T cell expansion while retaining robust humoral immunity. Remarkably, mRNA-PLNP vaccines generated approximately 50% more antigen-specific CD8+ T cells than mRNA-LNP vaccines across multiple antigens, including SARS-CoV-2 spike, influenza hemagglutinin, and ovalbumin. In prophylactic applications, mRNA PLNP vaccine provided complete protection against SARS-CoV-2 variants. As a therapeutic approach in a melanoma model, mRNA PLNP vaccination resulted in enhanced tumor control and significantly prolonged survival compared to LNP-based formulations. Collectively, these results establish PLNP as a versatile and broadly applicable platform for augmenting mRNA vaccine efficacy through improved mRNA delivery and T cell priming, offering promising implications for infection prevention and cancer immunotherapy.

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Cai, X., Chen, M., Cao, G., Asby, N., Elli, D., Gula, H., Nicolaescu, V., Nguyen, D.-T., Huang, X., Dangi, T., Solanki, A., Woessner, S., Zhang, W., Tang, E., Volpatti, L., Wallace, R., Pan, T., Nguyen, M., Chen, Q., Geng, Z., Sagar, R., Esser-Khan, A., Penaloza-MacMaster, P., Missiakas, D., Huang, J.. 2026-01-24. Polymer-lipid hybrid nanoparticle enhances mRNA delivery and T cell-mediated immunity. https://doi.org/10.64898/2026.01.22.701138

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