Systemic delivery of small interfering RNA targeting the interleukin-2/15 receptor β chain prevents disease...

Area of Science:

• Immunology
• Rheumatology
• Nanomedicine

Background:

• Interleukin-15 (IL-15) plays a key role in rheumatoid arthritis (RA) pathogenesis.
• Systemic knockdown of the IL-15 receptor (IL-15R) has not been previously demonstrated for local inflammation reduction.

Purpose of the Study:

• To investigate the therapeutic potential of siRNA targeting the IL-15 receptor beta chain (IL-2/15Rβ) delivered via nanoparticles.
• To evaluate the efficacy of this targeted therapy in reducing inflammation and disease progression in a rat model of adjuvant-induced arthritis (AA).

Main Methods:

• Intravenous administration of polyethylenimine (PEI)-complexed siRNA nanoparticles targeting IL-2/15Rβ in rats with AA.
• Assessment of nanoparticle accumulation in arthritic paws and uptake by immune cells (macrophages and T cells).
• Evaluation of clinical, radiological, and histological disease features, alongside proinflammatory mediator expression.

Main Results:

• PEI-complexed siRNA nanoparticles effectively accumulated in arthritic paws and were internalized by macrophages and T cells.
• Weekly administration of IL-2/15Rβ siRNA polyplexes significantly reduced disease progression in AA rats.
• Therapeutic effects included inhibition of clinical, radiological, and histological signs of RA, correlating with reduced inflammatory mediators.

Conclusions:

• Targeting IL-2/15Rβ with siRNA nanoparticles represents a viable therapeutic strategy for rheumatoid arthritis.
• This approach demonstrates successful local inflammation reduction through systemic administration, offering a promising avenue for RA treatment.