ACS nanoAug 11, 2026

Direct Lung Delivery of mRNA Nanoparticles Reprograms Lung Immune Cells for Lung Cancer Immunotherapy

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 12, 2026

Abstract

Intratracheal administration of mRNA-LNP vaccines enhances functional mRNA transfection efficiency in alveolar macrophages by 26.8-fold compared to intranasal delivery.

Intratracheal delivery results in a 2.6-fold increase in total pulmonary protein expression compared to intranasal delivery.
Alveolar macrophages, the primary antigen-presenting cells in the alveolar space, show significantly improved mRNA transfection efficiency with intratracheal administration.
This selective targeting reprograms alveolar macrophages, promoting effective antigen presentation and robust CD8+ T-cell responses.
Intratracheal vaccination demonstrates superior prophylactic and therapeutic efficacy in pulmonary tumor models.
Depleting alveolar macrophages completely negates the antitumor protection provided by intratracheal vaccination.

Simplified

Pulmonary delivery of lipid nanoparticle (LNP)-based mRNA vaccines offers a promising strategy for localized lung cancer immunotherapy, yet how distinct pulmonary administration routes determine cellular targeting and therapeutic efficacy remains poorly understood. Here, we systematically evaluate intranasal and intratracheal delivery of mRNA-LNP vaccines and reveal a route-dependent immunological mechanism governing lung-targeted tumor vaccination. Although intratracheal administration yields only a 2.6-fold increase in total pulmonary protein expression compared to intranasal delivery, it produces a striking 26.8-fold enhancement in functional mRNA transfection efficiency within alveolar macrophages, the dominant antigen-presenting cell population in the alveolar space. This selective targeting reprograms alveolar macrophages toward an activated antigen-presenting phenotype, promoting efficient antigen presentation, robust CD8+ T-cell responses, and superior prophylactic and therapeutic efficacy in pulmonary tumor models. Notably, local depletion of alveolar macrophages completely abolishes the antitumor protection conferred by intratracheal vaccination, establishing their indispensable role in mediating pulmonary mRNA vaccine efficacy. Together, these findings provide mechanistic insights into lung-targeted mRNA cancer vaccination driven by alveolar macrophage engagement, providing critical insights for the design of next-generation LNP-based nanomedicines for lung cancer immunotherapy.

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Direct Lung Delivery of mRNA Nanoparticles Reprograms Lung Immune Cells for Lung Cancer Immunotherapy

Abstract

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