A neutrophil mimicking metal-porphyrin-based nanodevice loaded with porcine pancreatic elastase for cancer therapy

Porcine neutrophil elastase (PPE) has been demonstrated to have a histone H1 isoform dependent anti-tumour effect. Here, the authors develop a biomimetic nanoplatform combining PPE and elevated histone H1 release induced by porphyrin nuclear localisation signal peptide and demonstrate its efficacy in preclinical cancer models. Precise discrimination and eradication of cancer cells by immune cells independent of antigen recognition is promising for solid tumor therapeutics, yet remains a tremendous challenge. Inspired by neutrophils, here we design and construct a tumor discrimination nanodevice based on the differential histone H1 isoform expression. In this nanodevice, neutrophil membrane camouflage and glutathione (GSH)-unlocking effect on Fe-porphyrin metal-organic framework structure ensures selectivity to cancer cells. The released porcine pancreatic elastase (PPE) simulates neutrophils' action to induce histone H1 release-dependent selective cancer cell killing. Meanwhile, nuclear localization signal (NLS) peptide-tagged porphyrin (porphyrin-NLS) acts as in-situ singlet oxygen (O-1(2)) generator to amplify histone H1 nucleo-cytoplasmic translocation by inducing DNA double-strand breaks (DSBs) under laser irradiation, further promoting elimination of cancer cells. The overexpressed histone H1 isoform in cancer cells improves selectivity of our nanodevice to cancer cells. In vivo studies demonstrate that our design can not only inhibit primary tumor growth, but also induce adaptive T-cell response-mediated abscopal effect to against distal tumors.

Automated summary

The authors develop a biomimetic nanoplatform combining porcine neutrophil elastase (PPE) and elevated histone H1 release for cancer treatment. This nanoplatform selectively targets and kills cancer cells through the release of PPE and induction of histone H1 release. In preclinical cancer models, it inhibits primary tumor growth and induces an adaptive T-cell response against distal tumors.