Nanoenabled IL-15 Superagonist via Conditionally Stabilized Protein-Protein Interactions Eradicates Solid Tumors by...

Area of Science:

• Biotechnology
• Nanotechnology
• Immunotherapy

Background:

• Protein complexes are vital for biological processes but often unstable for therapeutic use.
• Developing stabilized protein formulations is crucial for effective therapies.
• Targeted delivery systems are needed to enhance therapeutic efficacy and reduce side effects.

Purpose of the Study:

• To create a novel nanoformulation for stabilizing protein complexes using a pH-sensitive polymeric cloak.
• To develop an interleukin-15 (IL-15) nanosuperagonist (Nano-SA) for targeted cancer therapy.
• To evaluate the in vivo efficacy and safety of the Nano-SA in preclinical cancer models.

Main Methods:

• A functional polymeric cloak was designed to anchor and stabilize protein complex domains into a nanoformulation.
• The polymer-protein association was engineered to be pH-sensitive for targeted release in acidic tumor microenvironments.
• The interleukin-15 (IL-15)/IL-15 Receptor α (IL-15Rα) complex (IL-15cx) was encapsulated to create the IL-15 nanosuperagonist (Nano-SA).
• Nano-SA was administered intravenously and evaluated in murine colon cancer models.

Main Results:

• The Nano-SA demonstrated stable circulation and protected the IL-15cx integrity until reaching the tumor site.
• Selective release of the active IL-15cx in the tumor microenvironment amplified antitumor immune signals.
• Significant tumor eradication was achieved in murine colon cancer models with no observed adverse side effects.
• The Nano-SA effectively diminished systemic off-target effects.

Conclusions:

• The developed pH-sensitive polymeric cloak effectively stabilizes protein complexes for therapeutic applications.
• The IL-15 nanosuperagonist (Nano-SA) shows potent immunotherapeutic effects against cancer by targeting tumor sites.
• Nanotechnology offers a promising strategy for advancing protein complex-based therapies with improved efficacy and safety.