Dual-Responsive Immunomodulatory RNAi Nanoplatform for Effective Immune Checkpoint Blockade and Enhanced Cancer...

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Immune checkpoint blockade (ICB) therapy is a first-line cancer treatment, but low response rates persist.
• Metformin, an anti-hyperglycemic drug, shows anticancer potential by modulating the tumor immune microenvironment (TIME).
• Combining ICB with metformin is promising but limited by metformin's bioavailability and side effects.

Purpose of the Study:

• To design a dual-responsive immunomodulatory RNAi nanoplatform for enhanced cancer immunotherapy.
• To overcome metformin's limitations by creating a prodrug delivery system.
• To evaluate the nanoplatform's efficacy in breast cancer models.

Main Methods:

• Designed an amphiphilic, reduction-responsive metformin prodrug.
• Complexed metformin prodrug with small interfering RNA (siRNA).
• Co-assembled with endosomal pH-responsive PEGylated polymer to form a dual-responsive nanoplatform.
• Utilized orthotopic and metastatic breast cancer models for in vivo studies.

Main Results:

• The nanoplatform effectively silenced PD-L1 expression and suppressed breast cancer cell proliferation via AMP-activated protein kinase (AMPK) activation.
• AMPK activation reduced tumor-derived TGF-β and IL-6 secretion.
• Enhanced dendritic cell maturation, CD8+ T cell activation, and reduced infiltration of Tregs, MDSCs, and TAMs.
• Achieved significant inhibition of breast cancer tumor growth.

Conclusions:

• The developed dual-responsive RNAi nanoplatform is a promising strategy for enhancing cancer immunotherapy.
• This approach effectively delivers metformin and siRNA, overcoming delivery challenges.
• The nanoplatform demonstrates significant therapeutic potential for breast cancer treatment by modulating the tumor immune microenvironment.