Disrupting Complement-Inflammation Positive Feedback Circuit via Oligonucleotide Hydrogel Microspheres for Reversing...

Area of Science:

• Biomedical Engineering
• Immunology
• Rheumatology

Background:

• Chronic joint inflammation, such as rheumatoid arthritis (RA), involves a detrimental feedback loop between the complement system and inflammatory immune responses.
• Sustained immune microenvironment dysregulation in RA amplifies complement activation, creating a pathological cycle that worsens disease progression.

Purpose of the Study:

• To develop and evaluate MMP-9-responsive, injectable micro-nano geneplexes for targeted regulation of complement component C5.
• To investigate the potential of these geneplexes in disrupting the complement-inflammation circuit and treating chronic joint inflammation in RA.

Main Methods:

• Development of micro-nano geneplexes (C5ASO@HAP-CL-TIMP@HMs) by loading C5 antisense oligonucleotides (C5ASO) into cationic liposomes and encapsulating them within hyaluronic acid microspheres.
• In vitro assessment of geneplex efficacy in RA synoviocytes, including blocking C5 activation, restoring macrophage balance, and modulating cytokine profiles.
• In vivo evaluation using an adjuvant-induced arthritis rat model to assess therapeutic effects on joint swelling, cartilage degradation, and inflammatory responses.

Main Results:

• In vitro studies demonstrated that the geneplexes effectively inhibited abnormal C5 activation, rebalanced macrophage polarization, reduced pro-inflammatory mediators, and increased anti-inflammatory factors in RA synoviocytes.
• In vivo experiments showed significant reduction in joint swelling and cartilage damage, along with suppressed inflammatory responses in the adjuvant-induced arthritis rat model.
• The results highlight the geneplexes' capability to dismantle the complement-inflammation circuit, indicating their therapeutic potential.

Conclusions:

• The developed micro-nano geneplexes provide a novel strategy for on-demand regulation of complement component C5.
• These geneplexes show significant therapeutic promise for targeted treatment of chronic joint inflammation by disrupting the complement-inflammation feedback loop in RA.
• This approach offers a new perspective for managing RA and related chronic inflammatory joint diseases.