Cancer, a leading cause of mortality worldwide[1], poses a formidable challenge for treatment due to the complexity of the tumor microenvironment (TME). The TME comprises various cellular and non-cellular components[2], such as immune cells, endothelial cells, exosomes, enzymes, cytokines, growth factors, and extracellular matrix (ECM). The TME also exhibits distinctive features[3], such as hypoxia, altered pH, high ATP concentration, and abundant tumor microvasculature. These factors modulate the phenotype of tumor cells, resulting in drug resistance, cancer progression, and metastasis[4,5]. Hence, therapeutic approaches that target the TME have gained increasing attention.

Chemotherapy, radiotherapy, and surgery are essential and irreplaceable modalities for treating malignant tumors. However, they often fall short of optimal outcomes due to drug resistance and other limitations[6]. A novel strategy that can circumvent tumor drug resistance is plasma membrane rupture (PMR)[7]. PMR molecules have a similar amphiphilic structure, comprising cationic and hydrophobic moieties[8]. The cationic residues interact strongly with the negatively charged cell membrane of cancer cells, while the hydrophobic region penetrates the phospholipid bilayer, causing a detergent-like membrane disruption effect. PMR-induced cell death can bypass the intracellular signaling pathways of target cells, disregard their resistance profile and metabolic heterogeneity, and offer a promising strategy for tumor treatment[9].

Peptides are potential agents for tumor treatment due to their good biocompatibility. Compared with other anti-cancer strategies that rely on biomacromolecules, peptide-based methods have various advantages in cancer treatment, such as higher specificity, lower toxicity to normal tissues, and multifunctionality against cancer progression[10,11]. However, peptides also have drawbacks such as poor stability, short half-life, and easy degradation by proteases[12]. These limitations can be overcome by using methods such as chemical modification or material encapsulation, which can markedly enhance their biological stability [13]and make them more suitable for tumor treatment.

We proposed a peptide-based amphiphilic block copolymer-W6-H5-PLGLAG-PEG8 (pTrp-pHis-PLGLAG-PEG8) to specifically kill cancer cells, based on the above principles. This block copolymer has amphiphilic properties, which enable it to self-assemble into nanomicelles under physiological conditions. Due to the shielding of PEG, its intact structure can significantly reduce cytotoxicity and accumulate near tumor cells through enhanced permeability and retention effect (EPR effect)[14,15]. PLGLAG in the pTrp-pHis-PLGLAG-PEG8 sequence is a sensitive sequence linker for MMP-2 enzyme, which connects W6-H5 (pTrp-pHis) with cytotoxicity and PEG8 segment with good hydrophilicity and biocompatibility. In the tumor microenvironment, the nanostructure disintegrates under the synergistic response of high MMP-2 enzyme and acidic pH value, exposing the pTrp-pHis. The positively charged histidine binds to the negatively charged tumor cell membrane by electrostatic interaction, while the hydrophobic tryptophan inserts into the cell membrane, eventually inducing tumor cell death mediated by plasma membrane rupture (PMR).

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