Chiral Protein Supraparticles for Tumor Suppression and Synergistic Immunotherapy: An Enabling Strategy for Bioactive Supramolecular Chirality Construction.

Abstract

The design of bioactive supramolecular chirality is always hampered by the lack of feasible schemes to assigned specific biological activities. Herein, we developed a "mirror-image peptide grafting" method to graft the epitopes of bioactive d-peptide onto the miniprotein template to construct a self-assembled supraparticle. Grafting DPMIβ, a 12-mer d-enantiomeric peptide functioned as the p53 agonist, onto Apamin, we successfully constructed a self-assembled d-enantiomeric miniprotein supermolecule nanoparticle, termed DMSN. This chiral supraparticle possesses a favorable pharmaceutical profile including the passive tumor targeting, cell membrane penetration, intracellular reductive responsiveness, and endosome escaping. DMSN showed in vitro and in vivo p53-dependent antiproliferative activity and augmented antitumor immunity elicited by anti-PD1 therapy. This enabling strategy will allow us to fabricate a class of peptide/protein-derived supramolecular chirality with predictable biological activities and will likely have a broad impact on the chiral nanotechnology at the service of prevention and treatment of human diseases.