In Vivo Self-Sorting\nof Peptides via <i>In Situ</i> Assembly Evolution

Despite significant progress achieved\nin artificial self-sorting\nin solution, operating self-sorting in the body remains a considerable\nchallenge. Here, we report an in vivo self-sorting peptide system\nvia an in situ assembly evolution for combined cancer therapy. The\npeptide <b>E3C16-SS-EIY</b> consists of two disulfide-connected\nsegments, <b>E3C16SH</b> and <b>SHEIY</b>, capable of\nindependent assembly into twisted or flat nanoribbons. While <b>E3C16-SS-EIY</b> assembles into nanorods, exposure to glutathione\n(GSH) leads to the conversion of the peptide into <b>E3C16SH</b> and <b>SHEIY</b>, thus promoting in situ evolution from the\nnanorods into self-sorted nanoribbons. Furthermore, incorporation\nof two ligand moieties targeting antiapoptotic protein XIAP and organellar\nendoplasmic reticulum (ER) into the self-sorted nanoribbons allows\nfor simultaneous inhibition of XIAP and accumulation surrounding ER.\nThis leads to the cytotoxicity toward the cancer cells with elevated\nGSH levels, through activating caspase-dependent apoptosis and inducing\nER dysfunction. In vivo self-sorting of <b>E3C16-SS-EIY</b> decorated\nwith ligand moieties is thoroughly validated by tissue studies. Tumor-bearing\nmouse experiments confirm the therapeutic efficacy of the self-sorted\nassemblies for inhibiting tumor growth, with excellent biosafety.\nOur findings demonstrate an efficient approach to develop in vivo\nself-sorting systems and thereby facilitating in situ formulation\nof biomedical agents.