A biomimetic and self-assembled nanocluster targeting β-catenin for potent anti-cancer therapy and enhanced immunotherapy.

Immune checkpoint blockade therapies fail to induce immune response in the vast majority of cancer patients, so developing robust adjuvants for increasing tumor immune response is central for effective tumor immunotherapy. The Wnt/beta-catenin pathway is a crucial oncogenic signal in relation to tumor immune evasion; however, none of the Wnt inhibitor under clinical or preclinical phases has demonstrated satisfactory specificity. Thus, new compounds or modalities that tumor specifically modulate the Wnt signal will be of great significance and value in clinical tumor immunotherapy. Herein, inspired by a natural phenomenon in cancer cells that the Achilles' Heel of oncoprotein beta-catenin, H1 helix, predisposes beta-catenin to oligomerization for proteasomal degradation and can be exacerbated by carnosic acid (CA, a Wnt inhibitor), we developed a size-tuned nanocluster (CA(cluster)) with well-defined supramolecular nanostructure by coassembling CA and H1 peptide. With the inherent enhanced permeability and retention (EPR) effect and the designed tumor microenvironment (TME) responsiveness, the CA(cluster) tumor specifically suppress the Wnt/beta-catenin cascade in vivo, while maintaining a highly favorable biosafety profile. More importantly, the CA(cluster) in vivo improved the tumor response to the PD1/PD-L1 immune checkpoint blockade in melanoma and colon cancer. This study provides new insights into the biomimetic coassembly strategy to design supramolecular nanostructured adjuvants for hazard-free Wnt suppression and synergy with tumor immunotherapy.