Engineered Panax notoginseng polysaccharide micelles inhibit macrophage polarization and delay the progression of rheumatoid arthritis via JAK2-STAT3 signaling pathway
- J Nanobiotechnology. 2025 Jul 14;23(1):509. doi: 10.1186/s12951-025-03576-8.
- 1. College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, China.
- 2. Shenyang Key Laboratory of Chinese Medicine targeted Delivery Key Laboratory, Shenyang, 110148, China.
- 3. Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, Shanxi University of Chinese Medicine, Jinzhong, 030619, China.
- 4. Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, Shanxi University of Chinese Medicine, Jinzhong, 030619, China. [email protected].
- 5. College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, China. [email protected].
- 6. Shenyang Key Laboratory of Chinese Medicine targeted Delivery Key Laboratory, Shenyang, 110148, China. [email protected].
- # Contributed equally.
Background: The imbalance of macrophage polarization plays a pivotal role in the progression of rheumatoid arthritis (RA). Reprogramming macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype is considered a promising therapeutic strategy.
Methods: To address this challenge, Panax notoginseng Polysaccharides (PNP) with varying molecular weights were chemically conjugated with deoxycholic acid (DC) to obtain amphiphilic conjugates (PNP-DC), which self-assembled into micelles (PNP-Ms). After screening for optimal molecular weight, folic acid (FA) was introduced onto the micelle surface, and Polyphyllin I (PPI) was encapsulated to form FA-modified, PPI-loaded micelles (FA-PPI-Ms) with macrophage-targeting capability.
Results: FA-PPI-Ms showed enhanced cellular uptake via FA receptor-mediated endocytosis and effectively eliminated Reactive Oxygen Species (ROS), reduced inflammatory cytokine production, and exhibited good biosafety. In vivo, FA-PPI-Ms significantly alleviated joint swelling and inflammation in RA rat models. Mechanistic studies based on RNA Sequencing and experimental validation revealed that FA-PPI-Ms suppressed the JAK2/STAT3 signaling pathway, thereby promoting M2 macrophage polarization and restoring the M1/M2 balance.
Conclusion: This study presents a novel FA-PPI-Ms delivery system for targeted macrophages. By modulating polarization through inhibition of JAK2/STAT3 signaling, the system offers a promising therapeutic strategy for RA and potentially Other inflammatory diseases.