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

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.