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 GSHresponsive in situ self-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 via the design of two peptides E3C16E6 and EVM SeO derived from lipidinspired 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 situ self-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 situ self-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.
oxidizing reactions within cells and regulates a plethora of biological responses and events. [1,2] Due to the heterogeneity and complexity of tumor microenvironment (TME), intracellular redox buffer systems in tumor cells have better balance capacity for reactive oxygen species (ROS) and intracellular antioxidant. [3][4][5][6] More specifically, relatively high level of reducing substances, such as glutathione (GSH, 0.5−10 mm), can effectively control the ROS level below the lethal threshold to alleviate oxidative damage mediated tumor cell death, limiting cancer treatment efficacy. [7][8][9] Therefore, it is imperative to develop new strategies for destruction of redox homeostasis to improve the efficacy of ROS-mediated tumor therapy. In recent years, many strategies have been developed to improve the efficiency and efficacy of cancer therapy by disrupting the redox homeostasis, either by depleting reducing substances in TME or by generating ROS through some enzymatic/metal ion reactions. [10,11] In comparison, the generation of ROS along with the consumption of reducing substances can better disrupt the redox balance. In the last decade, except for conventional radiotherapy and chemotherapy, some emerging approaches, such as photodynamic therapy (PDT) and chemodynamic therapy (CDT), have been developed for tumor therapy through regulating redox homeostasis by promoting ROS production and consuming GSH. [12][13][14][15][16][17] Among them, CDT, a noninvasive tumor therapy strategy achieves tumor treatment by using the TMEassisted intratumoral Fenton/Fenton-like reaction for generating highly toxic hydroxyl radicals (•OH). [18][19][20][21][22] However, the limited intratumoral Fenton reaction efficiency restricts the therapeutic efficacy of CDT.Despite the rapid advances in emerging strategies, the most commonly used cancer treatment in the clinic is still chemotherapy. Unfortunately, the conventional therapeutic drugs of chemotherapy often suffer from nonspecific bio-distribution, leading to low bioavailability and severe side effects. [23,24] In addition, it is often difficult to completely eliminate tumors with only single type of therapy. [25][26][27] Therefore, development of nano-carriers for targeted synergistic therapy is promising for effective cancer treatment. In the past few decades, nanocarriers have been used as efficient drug delivery tool through
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