Drug resistance poses a persistent challenge in the context of advanced malignant tumor treatment. Within this arena, we report the self-assembly of a peptide-based block copolymer with the unique capability to trigger cell death across a wide spectrum of cancer cell phenotypes through plasma membrane rupture (PMR) upon stimuli from tumor microenvironment, such as pH and the overexpression of matrix metalloproteinase 2 (MMP2). The block copolymer consists of three distinct components: a hydrophobic poly(tyrosine)-block-poly(histidine) (pTrp-pHis) unit and a hydrophilic polyethylene glycol (PEG-8) segment, intricately linked by a MMP2-sensitive peptide linker (PLGLAG). This resulting block copolymer self assembles to generate nano-capsules of approximately 100 nm in diameter when introduced into an aqueous solution. The as-prepared nanocapsules maintain structural integrity and exhibit negligible cytotoxicity under normal physiologic condition. However, once the nanocapsules accumulate inside a tumor due to the enhanced permeability and retention (EPR) effect, cleavage of the block-copolymer by MMP2 and protonation of the pTrp-pHis block lead to collapse of the nanocapsules, releasing the cationic pTrp-pHis block into the tumor microenvironment. The released cationic pTrp-pHis blocks engage in stable electrostatic interaction with the negatively charged tumor cell membranes, eventually inducing PMR-mediated tumor cell death.

Our research unveils an innovative strategy for combating drug resistance in cancer therapy and holds the potential to address broader drug resistance challenges in the treatment of bacterial and fungal infections.