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

TL;DR

A new nanomicelle system combines chemotherapy, photodynamic therapy, and gas therapy to effectively target and suppress breast cancer growth.

Contribution

A cancer cell membrane-coated nanomicelle platform that synergizes chemotherapy, photodynamic therapy, and gas therapy for enhanced breast cancer treatment.

Findings

The nanomicelles achieved an 87.7% tumor weight suppression rate in vivo.

The system caused extensive necrosis, DNA fragmentation, and reduced Ki-67 proliferation markers.

Photodynamic therapy generated ROS and catalyzed L-Arg into antitumor nitric oxide.

Abstract

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.

Schematic illustration of CCM/IR780@Arg/ELP/Rapa preparation and membrane fusion, antitumor mechanisms involved after light irradiation.Image 1

•The cancer cell membrane coating enabled IR780 anchoring to cell membrane and cytosolic payload delivery.•During PDT, IR 780 generates ROS to damage cell membranes and catalyzes the conversion of L-Arg into NO.•Intracellular GSH cleaves the disulfide bonds of ELP/Rapa micelles, triggering rapamycin release.•Synergistic chemo-, photodynamic, and gas therapy achieved 87.7% tumor suppression.

The cancer cell membrane coating enabled IR780 anchoring to cell membrane and cytosolic payload delivery.

During PDT, IR 780 generates ROS to damage cell membranes and catalyzes the conversion of L-Arg into NO.

Intracellular GSH cleaves the disulfide bonds of ELP/Rapa micelles, triggering rapamycin release.

Synergistic chemo-, photodynamic, and gas therapy achieved 87.7% tumor suppression.

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