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Despite significant progress achieved in artificial self-sorting in solution, operating self-sorting in the body remains a considerable challenge. Here, we report an in vivo self-sorting peptide system via an in situ assembly evolution for combined cancer therapy. The peptide E3C16-SS-EIYconsists of two disulfide-connected segments, E3C16SHand SHEIY, capable of independent assembly into twisted or flat nanoribbons. While E3C16-SS-EIYassembles into nanorods, exposure to glutathione (GSH) leads to the conversion of the peptide into E3C16SHand SHEIY, thus promoting in situ evolution from the nanorods into self-sorted nanoribbons. Furthermore, incorporation of two ligand moieties targeting antiapoptotic protein XIAP and organellar endoplasmic reticulum (ER) into the self-sorted nanoribbons allows for simultaneous inhibition of XIAP and accumulation surrounding ER. This leads to the cytotoxicity toward the cancer cells with elevated GSH levels, through activating caspase-dependent apoptosis and inducing ER dysfunction. In vivo self-sorting of E3C16-SS-EIYdecorated with ligand moieties is thoroughly validated by tissue studies. Tumor-bearing mouse experiments confirm the therapeutic efficacy of the self-sorted assemblies for inhibiting tumor growth, with excellent biosafety. Our findings demonstrate an efficient approach to develop in vivo self-sorting systems and thereby facilitating in situ formulation of biomedical agents.

Self-sorting is a common phenomenon in eukaryotic cells and represents one of the versatile strategies for the formation of advanced functional materials; however, developing artificial self-sorting assemblies within living cells remains challenging. Here, we report on the GSH-responsive in situself-sorting peptide assemblies within cancer cells for simultaneous organelle targeting to promote combinatorial organelle dysfunction and thereby cell death. The self-sorting system was created viathe design of two peptides E3C16E6 and EVMSeOderived from lipid-inspired peptide interdigitating amphiphiles and peptide bola-amphiphiles, respectively. The distinct organization patterns of the two peptides facilitate their GSH-induced self-sorting into isolated nanofibrils as a result of cleavage of disulfide-connected hydrophilic domains or reduction of selenoxide groups. The GSH-responsive in situself-sorting in the peptide assemblies within HeLa cells was directly characterized by super-resolution structured illumination microscopy. Incorporation of the thiol and ER-targeting groups into the self-sorted assemblies endows their simultaneous targeting of endoplasmic reticulum and Golgi apparatus, thus leading to combinatorial organelle dysfunction and cell death. Our results demonstrate the establishment of the in situself-sorting peptide assemblies within living cells, thus providing a unique platform for drug targeting delivery and an alternative strategy for modulating biological processes in the future.