Journal of controlled release : official journal of the Controlled Release SocietyDec 10, 2025

Lung immune cell-targeted RNA delivery using special lipid particles may improve lung cancer immunotherapy

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Mannose-modified SORT lipid nanoparticles co-delivering SPP1-siRNA and IFN-gamma mRNA reprogrammed SPP1 macrophages and improved lung cancer immunotherapy responses in models.

Evidence

This formulation and preclinical cancer study engineered lung-restricted macrophage-targeted LNPs and tested them with immune checkpoint inhibitors in orthotopic lung cancer and pulmonary metastasis models.

Caveat

The claimed conversion of ICI non-responders into long-term survivors is still model-based, with no human clinical response data in the abstract.

Simplified

Neoadjuvant immunotherapy has transformed perioperative approaches for resectable non-small cell lung cancer (NSCLC) by stimulating anti-tumor immunity preoperatively; however, approximately 50 % of patients fail to show clinical responses. Single-cell RNA sequencing identifies SPP1macrophages as a significant obstacle in NSCLC immunotherapy, yet scarce researches have focused on selectively targeting this subset. Herein, we engineer mannose-modified selective organ-targeting lipid nanoparticles (SORT LNPs) that co-load SPP1-siRNA and interferon-γ (IFN-γ) mRNA (siSPP1-mIFNγ@mLNPs) for lung-restricted, mannose receptor-guided delivery to SPP1macrophages. Co-encapsulation of siSPP1 and mIFNγ mRNA within mLNPs yields a synergistic effect that surpasses individual encapsulation, as it reverses the M2-like properties of SPP1macrophages, diminishes their tumor-promoting functions, and reprograms them towards a tumoricidal phenotype. When combined with the immune checkpoint inhibitors (ICIs) in vivo, siSPP1-mIFNγ@mLNPs significantly boost anti-tumor immune responses in both orthotopic lung cancer and pulmonary metastases. Overall, siSPP1-mIFNγ@mLNPs present innovative perspectives for precise cell-type targeting strategies and position SPP1macrophage reprogramming as a clinically actionable strategy to convert ICI non-responders into long-term survivors. + + + +