Microenvironment-Triggered Sequentially Targeted Micelles for Dual Regulation of Macrophages and Fibroblast-Like Synoviocytes via ROS-Responsive Rg1 Release and HAP-1-Mediated Celastrol Delivery in Rheumatoid Arthritis Therapy.
- 1College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, People's Republic of China.
- 2Department of Pharmacy, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, People's Republic of China.
Abstract
Introduction
Excessive proliferation of invasive fibroblast-like synoviocytes (FLS) and persistent synovial inflammation inevitably drive the pathological progression of rheumatoid arthritis (RA). A drug delivery system enabling dual regulation of macrophages and FLS is highly desirable for RA treatment.Methods
We fabricated microenvironment-triggered sequentially targeted micelles (HAP@CMR) co-loaded with ginsenoside Rg1 (Rg1) and celastrol (Cel) for dual regulation of macrophages and FLS. Rg1 was conjugated to the micelle surface via a ROS-responsive linker. Within the ROS-overexpressing joint microenvironment, ROS-triggered cleavage of the Rg1 shell unmasked the HAP-1 targeting peptide to facilitate FLS endocytosis alongside selective Rg1 release, which suppressed macrophage-mediated inflammation. Cel was selectively internalized by FLS through the exposed HAP-1 peptide to inhibit FLS proliferation.Results
In vitro, HAP@CMR repolarized macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, suppressed inflammatory cytokine secretion, and exerted potent inhibitory effects on the proliferation, migration, and invasion of FLS. In a rat collagen-induced arthritis (CIA) model, administration of HAP@CMR led to the most pronounced reduction in paw swelling among all drug-treated groups. Further histological, X-ray, and micro-CT assessments confirmed that this treatment effectively alleviated synovial inflammation, attenuated cartilage erosion, and inhibited bone destruction.Conclusion
This novel nanoplatform promotes FLS apoptosis while mitigating local inflammatory responses, providing a promising therapeutic strategy for RA.
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BibTeX
@article{zhang2026microenvironmenttriggered,
title = {{Microenvironment-Triggered Sequentially Targeted Micelles for Dual Regulation of Macrophages and Fibroblast-Like Synoviocytes via ROS-Responsive Rg1 Release and HAP-1-Mediated Celastrol Delivery in Rheumatoid Arthritis Therapy.}},
author = {Yani Zhang and Ruibo Guo and Ying Zheng and Ge Zhang and Yifei Gao and Ziyan Hua and Bangyun Liu and Xuetao Li and Yuanyuan Wang and Liang Kong},
journal = {International journal of nanomedicine},
year = {2026},
month = oct,
doi = {10.2147/ijn.s644123},
url = {https://europepmc.org/article/MED/42960261},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Microenvironment-Triggered Sequentially Targeted Micelles for Dual Regulation of Macrophages and Fibroblast-Like Synoviocytes via ROS-Responsive Rg1 Release and HAP-1-Mediated Celastrol Delivery in Rheumatoid Arthritis Therapy.
AU - Yani Zhang
AU - Ruibo Guo
AU - Ying Zheng
AU - Ge Zhang
AU - Yifei Gao
AU - Ziyan Hua
AU - Bangyun Liu
AU - Xuetao Li
AU - Yuanyuan Wang
AU - Liang Kong
PY - 2026
DA - 2026/10/25
JO - International journal of nanomedicine
DO - 10.2147/ijn.s644123
UR - https://europepmc.org/article/MED/42960261
AB - Introduction Excessive proliferation of invasive fibroblast-like synoviocytes (FLS) and persistent synovial inflammation inevitably drive the pathological progression of rheumatoid arthritis (RA). A drug delivery system enabling dual regulation of macrophages and FLS is highly desirable for RA treatment.Methods We fabricated microenvironment-triggered sequentially targeted micelles (HAP@CMR) co-loaded with ginsenoside Rg1 (Rg1) and celastrol (Cel) for dual regulation of macrophages and FLS. Rg1 was conjugated to the micelle surface via a ROS-responsive linker. Within the ROS-overexpressing joint microenvironment, ROS-triggered cleavage of the Rg1 shell unmasked the HAP-1 targeting peptide to facilitate FLS endocytosis alongside selective Rg1 release, which suppressed macrophage-mediated inflammation. Cel was selectively internalized by FLS through the exposed HAP-1 peptide to inhibit FLS proliferation.Results In vitro, HAP@CMR repolarized macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, suppressed inflammatory cytokine secretion, and exerted potent inhibitory effects on the proliferation, migration, and invasion of FLS. In a rat collagen-induced arthritis (CIA) model, administration of HAP@CMR led to the most pronounced reduction in paw swelling among all drug-treated groups. Further histological, X-ray, and micro-CT assessments confirmed that this treatment effectively alleviated synovial inflammation, attenuated cartilage erosion, and inhibited bone destruction.Conclusion This novel nanoplatform promotes FLS apoptosis while mitigating local inflammatory responses, providing a promising therapeutic strategy for RA.
SN - 1176-9114
SN - 1178-2013
ER -