Polymer-siRNA nanovectors for treating lung inflammation

Area of Science:

• Biomaterials Science
• Nanotechnology
• Pulmonary Medicine

Background:

• Uncontrolled lung inflammation drives many diseases, with current treatments causing side effects.
• Small interfering RNA (siRNA) offers therapeutic immune regulation but faces delivery challenges like cellular uptake and tissue localization.

Purpose of the Study:

• To investigate guanidinium-functionalized polymers (Cn-Guan) for optimizing siRNA delivery and efficacy in treating lung inflammation.
• To explore the impact of polymer amphiphilicity, side chain length, and molecular weight on siRNA complexation and therapeutic outcomes.

Main Methods:

• Synthesized nine Cn-Guan polymers with varying side chain lengths (C3, C5, C7) and molecular weights (17, 30, 65 kDa).
• Formed polyplexes with siRNA and characterized their size and complexation efficiency.
• Evaluated in vitro gene knockdown and in vivo lung accumulation and inflammation reduction in a murine model.

Main Results:

• C7-Guan/siRNA polyplexes showed the smallest size and tightest siRNA complexation.
• In vitro, 65 kDa polymers yielded highest knockdown; C3/C5-Guan/siRNA achieved ~70% knockdown.
• In vivo, C7-Guan/siRNA demonstrated superior lung accumulation and ~70% TNF-α knockdown at a low dose, suggesting enhanced serum stability.

Conclusions:

• Cn-Guan/siRNA polyplexes are effective and safe for attenuating pulmonary inflammation.
• Polymer properties significantly influence siRNA delivery and therapeutic efficacy.
• These findings provide insights for developing advanced siRNA delivery vectors for lung diseases.