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.

Lung metastasis is challenging in patients with triple‐negative breast cancer (TNBC). Surgery is always not available due to the dissemination of metastatic foci and most drugs are powerless because of poor retention at metastatic sites. TNBC cells generate an inflamed microenvironment and overexpress adhesive molecules to promote invasion and colonization. Herein, “walking dead” TNBC cells are developed through conjugating anti‐PD‐1 (programmed death protein 1 inhibitor) and doxorubicin (DOX)‐loaded liposomes onto cell corpses for temporal chemo‐immunotherapy against lung metastasis. The walking dead TNBC cells maintain plenary tumor antigens to conduct vaccination effects. Anti‐PD‐1 antibodies are conjugated to cell corpses via reduction‐activated linker, and DOX‐loaded liposomes are attached by maleimide–thiol coupling. This anchor strategy enables rapid release of anti‐PD‐1 upon reduction conditions while long‐lasting release of DOX at inflamed metastatic sites. The walking dead TNBC cells improve pulmonary accumulation and local retention of drugs, reprogram the lung microenvironment through damage‐associated molecular patterns (DAMPs) and PD‐1 blockade, and prolong overall survival of lung metastatic 4T1 and EMT6‐bearing mice. Taking advantage of the walking dead TNBC cells for pulmonary preferred delivery of chemotherapeutics and checkpoint inhibitors, this study suggests an alternative treatment option of chemo‐immunotherapy to augment the efficacy against lung metastasis.

The authors confirm that the PI for this paper is Rongsheng Zhao and that he had direct clinical responsibility for patients included in the study investigating the patients' willingness on individualized medication of high-dose methotrexate.