Bioinspired membrane-fusogenic nanomicelles for synergistic chemotherapy, photodynamic therapy, and gas therapy of breast cancer.

Breast cancer remains the most prevalent malignancy globally, posing significant therapeutic challenges. Although nanodelivery systems offer promising strategies for breast cancer therapy, their clinical translation is hindered by critical limitations, including suboptimal biocompatibility, rapid immune clearance, poor targeting specificity, inefficient cellular uptake, and inadequate endolysosomal escape. To overcome these barriers, a cancer cell membrane-coated elastin polypeptide (ELP)-based nanomicelle was designed. This nanomicelle intercalated the photosensitizer IR780 within its hydrophobic region of the cell membrane coating, while encapsulating both rapamycin (Rapa)-loaded ELP micelles and free L-arginine in the hydrophilic core. Benefiting from the homotypic membrane fusion capacity of the cell membrane coating, the nanomicelles enabled active targeting of breast cancer, anchoring IR780 to the breast cancer cell membrane, while releasing L-Arg and Rapa-loaded ELP micelles into the cytoplasm. Under NIR irradiation, IR780 triggered photodynamic therapy (PDT), generating reactive oxygen species (ROS) that simultaneously damaged tumor cell membranes and catalyzed L-Arg conversion to antitumor nitric oxide (NO) gas. Simultaneously, intracellular glutathione cleaved disulfide bonds in the corona of ELP micelles, enabling controlled Rapa release for chemotherapy. In vivo studies demonstrated potent antitumor efficacy of our nanomicelles, including a tumor weight suppression rate of 87.7 %, extensive necrosis, severe DNA fragmentation, and near-elimination of Ki-67 proliferation markers. This work establishes a cell membrane-camouflaged platform for synergistic chemotherapy, PDT, and gas therapy against breast cancer.