Traceable Bioinspired Nanoparticle for the Treatment of Metastatic Breast Cancer via NIR-Trigged Intracellular Delivery of Methylene Blue and Cisplatin.

Cytotoxic T lymphocyte (CTL) eliminates abnormal cells through target recognition-triggered intracellular toxin delivery. Chimeric antigen receptor T-cell improves cancer cell recognition of CTL, but its effectiveness and safety in solid tumor treatment are still hampered by poor tumor infiltration, suppressive tumor microenvironment, and severe on-target off-tumor toxicity. Given the functionality and challenges of CTL in cancer therapy, herein, a CTL-inspired nanovesicle (MPV) with a cell membrane-derived shell and a methylene blue (MB) and cisplatin (Pt) loaded gelatin nanogel core is created. The MPV generates contrast for tumor photoacoustic imaging, and produces hyperthermia upon laser irradiation, enabling photothermal imaging and deep tumor penetration. Meanwhile, it releases MB and Pt, and then delivers them into the cytosol of cancer cells, which process can be visualized by imaging the recovery of MB-derived fluorescence. The localized hyperthermia, photodynamic therapy, and chemotherapy together kill 4T1 breast cancer cells effectively, resulting in primary tumor regression and 97% inhibition of pulmonary metastasis, without significant toxicity to the animals. Taken together, the MPV shows tumor-specific and stimuli-triggered intracellular toxin delivery with advantages in traceable accumulation and activation, high tumor penetration, and triple combination therapy, and thus can be an effective nanomedicine for combating metastatic breast cancer.