Polymeric cloak stabilizes cytokine complex to generate tumor-targeted nanosuperagonist

Protein complexes are crucial orchestrators of biological processes that hold immense therapeutic potential. However, their instability and transient nature have hindered practical applications. This study introduces a pH-sensitive polymeric cloak that wraps and stabilizes protein complexes, enabling robust in vivo delivery. The efficacy of this system is clearly show using the interleukin-15 (IL-15)/IL-15 receptor-α domain (IL-15Rα) complex. The polymeric cloak reinforces the IL-15/IL-15Rα interaction and shields it from degradation in circulation. In the tumor microenvironment, the pH-sensitive properties of the cloak trigger its dissociation, liberating the complexes and enhancing IL-15 trans-presentation for superagonistic immune activation. This “nanosuperagonist” demonstrated powerful and safe immunotherapy against colon cancer in mice. The findings suggest that this approach could revolutionize the clinical translation of protein-complex-based therapeutics, opening new avenues for disease treatment.

Papers

Journal: Journal of American Chemical Society

Title: Nanoenabled IL-15 Superagonist via Conditionally Stabilized Protein–Protein Interactions Eradicates Solid Tumors by Precise Immunomodulation

Authors: Pengwen Chen, Shangwei Li, Koji Nagaoka, Kazuhiro Kakimi, Kazunori Kataoka*, Horacio Cabral*

DOI: 10.1016/j.corsci.2024.112329