Reprogramming M2 macrophages via TLR7/8 agonist-loaded hollow MnO₂ nanovehicles to suppress the progression of liver cancer
4 affiliations
- 1Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- 2Innovation Centre for Science and Technology of North Sichuan Medical College, Nanchong, Sichuan, China
- 3Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, North Sichuan Medical College, Nanchong, Sichuan Province, China
- 4Department of Ultrasound, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
Abstract
As a prevalent malignancy, liver cancer ranks as the third most common cause of cancer mortality globally. Within the tumor microenvironment, tumor-associated macrophages (TAMs) exhibit contrasting functional phenotypes: the anti-tumor M1 type and the pro-tumor M2 type. Reprogramming TAMs from the M2 to the M1 phenotype has emerged as a promising immunotherapeutic strategy. Here, we engineered a multi-nano therapeutic system, PAH@HMMDN@R848, by loading a TLR7/8 agonist (R848) onto hollow MnO2 nanoparticles (HMMDN) and coating with polyallylamine hydrochloride (PAH). In vitro, this system efficiently repolarized M2 macrophages to the M1 phenotype, evidenced by decreased CD206, Arg-1, IL-10 and increased CD80, iNOS, TNF-α (P < 0.05). Under acidic/glutathione-rich conditions, HMMDN degraded to release Mn2+, which served as a T1-weighted MRI contrast agent with a high relaxivity (r1 = 5.255 mM-1 s -1). Mechanistically, PAH@HMMDN@R848 activated both NF-κB (via R848) and STING (via Mn2+) pathways, leading to synergistic M1 polarization. In a subcutaneous H22 liver cancer mouse model, intratumoral injection of PAH@HMMDN@R848 significantly suppressed tumor growth (tumor inhibition rate 80.6%) without obvious systemic toxicity. Immunohistochemistry and cytokine analysis revealed that the treatment increased M1 macrophage infiltration (CD80+) and reduced M2 macrophages (CD206+) within tumors, along with elevated TNF-α/iNOS and decreased IL-10/Arg-1. This study presents a multifunctional nanoplatform capable of TAMs reprogramming and MRI diagnosis, offering a promising approach for liver cancer theranostics.
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BibTeX
@article{he2026reprogramming,
title = {{Reprogramming M2 macrophages via TLR7/8 agonist-loaded hollow MnO₂ nanovehicles to suppress the progression of liver cancer}},
author = {Pei-pei He and Zheng-ju Hou and Han-mei Li and Ji-xuan Zhang and An-Qi Chen and Quan-you Miao and Chao-Feng Yang and Jin-hong Yu and Yang Li},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0358567},
url = {https://doi.org/10.1371/journal.pone.0358567},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Reprogramming M2 macrophages via TLR7/8 agonist-loaded hollow MnO₂ nanovehicles to suppress the progression of liver cancer
AU - Pei-pei He
AU - Zheng-ju Hou
AU - Han-mei Li
AU - Ji-xuan Zhang
AU - An-Qi Chen
AU - Quan-you Miao
AU - Chao-Feng Yang
AU - Jin-hong Yu
AU - Yang Li
PY - 2026
DA - 2026/09/18
JO - PLOS One
DO - 10.1371/journal.pone.0358567
UR - https://doi.org/10.1371/journal.pone.0358567
AB - As a prevalent malignancy, liver cancer ranks as the third most common cause of cancer mortality globally. Within the tumor microenvironment, tumor-associated macrophages (TAMs) exhibit contrasting functional phenotypes: the anti-tumor M1 type and the pro-tumor M2 type. Reprogramming TAMs from the M2 to the M1 phenotype has emerged as a promising immunotherapeutic strategy. Here, we engineered a multi-nano therapeutic system, PAH@HMMDN@R848, by loading a TLR7/8 agonist (R848) onto hollow MnO2 nanoparticles (HMMDN) and coating with polyallylamine hydrochloride (PAH). In vitro, this system efficiently repolarized M2 macrophages to the M1 phenotype, evidenced by decreased CD206, Arg-1, IL-10 and increased CD80, iNOS, TNF-α (P < 0.05). Under acidic/glutathione-rich conditions, HMMDN degraded to release Mn2+, which served as a T1-weighted MRI contrast agent with a high relaxivity (r1 = 5.255 mM-1 s -1). Mechanistically, PAH@HMMDN@R848 activated both NF-κB (via R848) and STING (via Mn2+) pathways, leading to synergistic M1 polarization. In a subcutaneous H22 liver cancer mouse model, intratumoral injection of PAH@HMMDN@R848 significantly suppressed tumor growth (tumor inhibition rate 80.6%) without obvious systemic toxicity. Immunohistochemistry and cytokine analysis revealed that the treatment increased M1 macrophage infiltration (CD80+) and reduced M2 macrophages (CD206+) within tumors, along with elevated TNF-α/iNOS and decreased IL-10/Arg-1. This study presents a multifunctional nanoplatform capable of TAMs reprogramming and MRI diagnosis, offering a promising approach for liver cancer theranostics.
SN - 1932-6203
ER -