Fluorinated amphipathic cationic peptides for intracellular protein delivery and cancer immunotherapy

Cell penetrating peptides are widely developed as carriers to transport proteins inside cells, but there remain some drawbacks such as limited protein loading capacity and nanoparticle stability, endosomal escape and intracellular delivery efficacy. Herein, we design a family of fluorinated amphipathic cationic peptides (FACPs) to address these issues. A library of amphipathic cationic hexapeptides is conjugated with a fluorous tag at the C -terminus via a dynamic hydrazone bond. Among the investigated materials, FACP2 (peptide sequence: RRRWWW) demonstrates the optimal performance in protein binding, cellular uptake, endosomal escape, and thus intracellular delivery efficacy. It efficiently delivers ovalbumin into bone marrow derived dendritic cells and stimulates their maturation, enhancing the antigen cross-presentation both in vitro and in vivo . As a result, the FACP2/ovalbumin nanovaccine effectively inhibits the tumor growth in mice when combined with anti-PD1 therapy or co-delivered with the STING agonist 2′,3′-cyclic guanosine monophosphate. This study provides a highly efficient peptide nanocarrier for cytosolic protein delivery and cancer immunotherapy through antigen and adjuvant co-delivery.