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Inflammation-Responsive Nanocolloidal Hydrogel Enables On-Demand Gene Activation for Osteoarthritis Therapy
Yuexin Zhao1,2, Yang Song3, Yuling Shen2
1Taishan People's Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Taishan, China.
Abstract:
Synovitis-driven inflammation and oxidative stress are key drivers of osteoarthritis (OA) progression. As a master regulator of antioxidant and anti-inflammatory defenses, nuclear factor erythroid 2-related factor 2 (Nrf2) represents a promising therapeutic target. However, current strategies for Nrf2 activation remain limited in achieving durable synovial gene expression and pathology-adaptive release. Here, we developed an injectable inflammation-responsive nanocolloidal hydrogel enabling sustained and on-demand Nrf2 activation within OA joints. The hydrogel was fabricated by crosslinking polyvinyl alcohol (PVA) with phenylboronic acid (PBA)-functionalized nanoparticles encapsulating Nrf2 plasmids. Dynamic boronate ester linkages between PBA and PVA enabled rapid in situ gelation after intra-articular injection. In the ROS-enriched inflammatory microenvironment of OA, cleavage of boronate ester bonds triggered the release of Nrf2 plasmid-loaded nanoparticles. The released nanoparticles were efficiently internalized by fibroblast-like synoviocytes (FLSs) and promoted Nrf2 expression, thereby suppressing oxidative stress and inflammatory responses. In ACLT-induced OA mice, the hydrogel markedly alleviated synovial inflammation, preserved cartilage matrix, and reduced the OARSI score by approximately 70%. These findings highlight its potential as a promising strategy for inflammation-adaptive gene regulation in OA therapy.
Insights
This study introduces an injectable hydrogel that releases Nrf2 plasmids on-demand to combat osteoarthritis (OA) inflammation and oxidative stress. The novel hydrogel therapy significantly reduced OA progression in mice, offering a promising new treatment avenue.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Rheumatology
Background:
- Osteoarthritis (OA) progression is driven by synovitis-induced inflammation and oxidative stress.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant and anti-inflammatory pathways, making it a potential therapeutic target for OA.
- Current Nrf2 activation strategies face limitations in achieving sustained synovial gene expression and adaptive release in response to disease pathology.
Purpose of the Study:
- To develop an injectable, inflammation-responsive nanocolloidal hydrogel for sustained and on-demand Nrf2 activation within the joints of osteoarthritis patients.
- To investigate the hydrogel's ability to suppress oxidative stress and inflammation in fibroblast-like synoviocytes (FLSs) and alleviate OA symptoms in a preclinical mouse model.
Main Methods:
- Fabrication of an injectable hydrogel by crosslinking polyvinyl alcohol (PVA) with phenylboronic acid (PBA)-functionalized nanoparticles encapsulating Nrf2 plasmids.
- Utilizing dynamic boronate ester linkages for rapid in situ gelation upon intra-articular injection.
- Investigating the hydrogel's response to the reactive oxygen species (ROS)-rich OA microenvironment, triggering Nrf2 plasmid release and subsequent FLS uptake and activation.
Main Results:
- The hydrogel demonstrated rapid in situ gelation and inflammation-responsive release of Nrf2 plasmid-loaded nanoparticles in an OA-mimicking environment.
- In vitro studies showed efficient nanoparticle internalization by FLSs, leading to enhanced Nrf2 expression, suppressed oxidative stress, and reduced inflammatory responses.
- In vivo studies using ACLT-induced OA mice showed that the hydrogel significantly reduced synovial inflammation, preserved cartilage matrix, and decreased the Osteoarthritis Research Society International (OARSI) score by approximately 70%.
Conclusions:
- The developed inflammation-responsive nanocolloidal hydrogel provides a novel strategy for sustained and on-demand Nrf2 activation in OA joints.
- This approach effectively mitigates synovitis, oxidative stress, and cartilage degradation, highlighting its therapeutic potential for osteoarthritis.
- The study underscores the promise of inflammation-adaptive gene regulation using responsive hydrogel systems for treating OA and potentially other inflammatory joint diseases.
