Key Takeaways & Executive Findings
- •• • The nanoprobe achieved selective M1φ imaging via dual targeting of GLUTs and NO activation, with enhanced PA signal intensity correlating with M1φ abundance during NAFLD progression in diabetic mice (12-week vs. 19-week). • • In vivo PA imaging at 6 h post-injection distinguished NASH from NAFL based on distinct signal enhancement patterns, validated by histology (Oil Red O, H&E, Masson) and flow cytometry (F4/80+/CD86+ cell rates). • • The probe demonstrated high selectivity for NO, enabling specific imaging of M1φ over other macrophage phenotypes, reducing non-specific uptake and improving sensitivity. • • The study provides a non-invasive diagnostic strategy for NASH, potentially reducing reliance on liver biopsy and enabling longitudinal monitoring of disease progression.
Abstract
M1 macrophages (M1φ) are pivotal drivers in the progression from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). Longitudinal monitoring of intrahepatic M1φ could facilitate non-invasive diagnosis of NASH, yet achieving specific and sensitive in vivo imaging of M1φ remains challenging due to the nonspecific phagocytic activity common to all phenotypic macrophages. In this study, we developed a dual-target-recognizing photoacoustic nanoprobe that can target glucose transporters (GLUTs) and be selectively activated by nitric oxide (NO). Benefiting from its enhanced affinity for M1φ and decent responsive capability to NO, the probe exhibited favorable imaging performance toward M1φ in ex vivo experiments. Following systemic administration in diabetic mice, the probe rapidly accumulated in the liver, where it was selectively internalized by M1φ via specific recognition between glucose molecules and GLUTs, further inducing a NO-triggered enhancement of the photoacoustic signal. Distinct photoacoustic signal enhancement patterns were observed between NAFL and NASH livers, enabling non-invasive in vivo discrimination of NASH. This study proposes a novel strategy using a dual-target-recognizing probe to improve the selectivity and sensitivity of in vivo M1φ imaging, while also providing new insights for the non-invasive diagnosis of NASH.
1. Introduction
Non-alcoholic fatty liver disease (NAFLD) affects approximately 25% of the global population, with a spectrum ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH), a principal cause of cirrhosis and hepatocellular carcinoma. Current imaging modalities—ultrasound, 1H-MRS, and CT—are limited to quantifying steatosis and cannot reliably distinguish NASH from NAFL, necessitating invasive liver biopsy for definitive diagnosis. Biopsy carries procedural risks and sampling bias, underscoring an urgent need for non-invasive methods to detect NASH-specific inflammation.
Hepatic M1 macrophages (M1φ) are key drivers of NAFL-to-NASH progression, secreting pro-inflammatory cytokines. However, in vivo imaging of M1φ is hampered by the nonspecific phagocytic activity of all macrophages. This study introduces a dual-target-recognizing photoacoustic nanoprobe that exploits the overexpression of glucose transporters (GLUTs) on M1φ and the elevated nitric oxide (NO) production from inducible nitric oxide synthase (iNOS). The probe's glucose surface functionalization enhances M1φ affinity, while NO-triggered activation provides high specificity, enabling sensitive photoacoustic imaging to differentiate NASH from NAFL in a mouse model.
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Meng Zhang, Yiyue Wang, Qihong Wu, Ran Sun, Lu Ye, Lu Zhang, Julin Wang, Minrui Liu, Hanrui Liu, Haiming Fan, Yingkun Guo (2026). Visualizing hepatic M1 macrophages with a dual-target-recognizing photoacoustic nanoprobe for identifying non-alcoholic steatohepatitis. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-4080-y
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Frequently Asked Questions
What is the specificity of the nanoprobe for M1 macrophages over other phenotypes, and how was it quantified?
The nanoprobe's specificity was demonstrated through ex vivo experiments showing enhanced affinity for M1φ via GLUT targeting and NO activation. In vivo, PA signal enhancement correlated with F4/80+/CD86+ cell rates and iNOS expression, confirming selective M1φ imaging. Quantitatively, the probe showed significantly higher PA signal in NASH livers compared to NAFL, with signal enhancement factors increasing with disease progression (12-week vs. 19-week diabetic mice).
What is the detection limit or sensitivity of the photoacoustic imaging for M1φ in vivo?
The study does not specify an absolute detection limit, but the probe enabled clear discrimination between NAFL and NASH based on PA signal enhancement patterns. The sensitivity was sufficient to detect increasing M1φ populations during NAFLD progression, as validated by histology and flow cytometry.
How does the nanoprobe avoid non-specific uptake by other macrophage phenotypes?
The nanoprobe is surface-functionalized with glucose, which specifically binds to GLUTs overexpressed on M1φ, reducing uptake by M2φ and other macrophages. Additionally, the probe is activatable by NO, which is produced at high levels in M1φ, ensuring signal generation only in M1φ.
What is the time window for optimal imaging after injection?
In vivo PA imaging was performed 6 hours after intravenous injection, which allowed sufficient accumulation in the liver and internalization by M1φ. This time point provided clear signal enhancement differences between NAFL and NASH.
What are the potential clinical translation challenges for this nanoprobe?
Challenges include ensuring biocompatibility and long-term safety, scaling up synthesis, and validating efficacy in human subjects. The probe's dual-targeting strategy may require optimization for human GLUT and NO levels. Additionally, photoacoustic imaging systems need to be clinically available for liver imaging.
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