Modeling lung adenocarcinoma using layer-by-layer nanoparticles mitigates innate immune cell activation
- 1Massachusetts Institute of Technology
Abstract
Lung adenocarcinoma, driven frequently by KRAS and p53 mutations, remains a leading cause of cancer mortality. Current state-of-the-art genetically engineered mouse models often rely on viral delivery of recombinases, such as Cre recombinase, to initiate transformation. However, viral particles can infect and activate innate immune cells, thus potentially impacting studies of tumor-immune dynamics. Here, we develop a layer-by-layer (LbL) polyplex platform using poly({beta}-aminoester) (PBAE) polymers layered with poly-L-aspartic acid (PLD) to deliver Cre mRNA to lungs while avoiding immune cell transfection and activation. PLD-coated nanoparticles (PLD-NPs) exhibit stable mRNA encapsulation and efficient transfection in vitro, even after lyophilization and long-term storage. In KrasLSL-G12D/+;p53flox/flox (KP) mice, PLD-NPs initiate lung adenocarcinomas that mirror human histopathology without infecting or activating dendritic cells and alveolar macrophages, unlike lentiviral (LV) or adenoviral delivery methods. Single-cell transcriptional profiling revealed that LV administration drives long-term upregulation of antigen presentation and costimulatory machinery in lung-resident myeloid populations. This persistent immune activation is avoided by NP delivery. By uncoupling tumor initiation from innate immune activation, this platform enables the high-fidelity interrogation of tumor-immune dynamics, especially for non-inflammation-driven lung cancer.
Related
- Cross-Dataset Reanalysis of Mouse Alzheimer Disease Single-Cell RNA-Sequencing Data Reveals a Reproducible Innate Immune Activation Signature
- 981 Tumor-mediated innate training of neutrophil progenitors involves FOXO1 activation and promotes immunotherapy-associated colitis
- Single-Cell Profiling Reveals Innate Lymphoid Cells and OX40 Activation in Breast Cancer-Related Lymphedema
- 840 Cleavable albumin-hitchhiking STING agonists for innate immune activation and combination with adoptive cell therapy in solid tumors
- CB2 activation during epileptogenesis recruits immunomodulatory monocytes and mitigates cognitive, affective and seizure outcomes
BibTeX
@misc{bhandarkar2026modeling,
title = {{Modeling lung adenocarcinoma using layer-by-layer nanoparticles mitigates innate immune cell activation}},
author = {V. Bhandarkar and E. Torres-Mejia and T. Heim and N. Nabar and T. G. Dacoba and Z. Rogers and N. Mathey-Andrews and S.-L. Shanahan and C. Vo and A. Berger and J. C. Love and T. Jacks and P. T. Hammond and S. Spranger},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.14.751530},
url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751530v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Modeling lung adenocarcinoma using layer-by-layer nanoparticles mitigates innate immune cell activation
AU - V. Bhandarkar
AU - E. Torres-Mejia
AU - T. Heim
AU - N. Nabar
AU - T. G. Dacoba
AU - Z. Rogers
AU - N. Mathey-Andrews
AU - S.-L. Shanahan
AU - C. Vo
AU - A. Berger
AU - J. C. Love
AU - T. Jacks
AU - P. T. Hammond
AU - S. Spranger
PY - 2026
DA - 2026/09/14
PB - bioRxiv
DO - 10.64898/2026.09.14.751530
UR - https://www.biorxiv.org/content/10.64898/2026.09.14.751530v1
AB - Lung adenocarcinoma, driven frequently by KRAS and p53 mutations, remains a leading cause of cancer mortality. Current state-of-the-art genetically engineered mouse models often rely on viral delivery of recombinases, such as Cre recombinase, to initiate transformation. However, viral particles can infect and activate innate immune cells, thus potentially impacting studies of tumor-immune dynamics. Here, we develop a layer-by-layer (LbL) polyplex platform using poly({beta}-aminoester) (PBAE) polymers layered with poly-L-aspartic acid (PLD) to deliver Cre mRNA to lungs while avoiding immune cell transfection and activation. PLD-coated nanoparticles (PLD-NPs) exhibit stable mRNA encapsulation and efficient transfection in vitro, even after lyophilization and long-term storage. In KrasLSL-G12D/+;p53flox/flox (KP) mice, PLD-NPs initiate lung adenocarcinomas that mirror human histopathology without infecting or activating dendritic cells and alveolar macrophages, unlike lentiviral (LV) or adenoviral delivery methods. Single-cell transcriptional profiling revealed that LV administration drives long-term upregulation of antigen presentation and costimulatory machinery in lung-resident myeloid populations. This persistent immune activation is avoided by NP delivery. By uncoupling tumor initiation from innate immune activation, this platform enables the high-fidelity interrogation of tumor-immune dynamics, especially for non-inflammation-driven lung cancer.
ER -