Localized Degradation of Neutrophil Extracellular Traps by Photoregulated Enzyme Delivery for Cancer Immunotherapy and Metastasis Suppression

Extrusion of neutrophil extracellular traps (NETs), a fundamental host innate immune defense against pathogens, has recently been linked to cancer resistance to immunotherapy and distant metastasis. These findings highlight interesting areas of cancer-elicited inflammation and potential therapeutic strategies. Disrupting existing NETs with DNase I has been proved to enhance the therapeutic efficacy of tumor immunotherapy and attenuate metastatic spread. However, systemic biodistribution of DNase I raises safety issues, potentially impairing host defense against infection. Hence, tumor-specific delivery and metastatic niche-targeted effects are attractive options for localized degradation of NETs. We have engineered a nanoplatform with a plasmonic gold blackbody (AuPB) core with broad-spectrum photo activity and a mesoporous polydopamine (mPDA) shell for efficient loading and photoregulated release of DNase I. The on-demand released DNase I triggered by the second near-infrared (NIR-II) light irradiation breaks the “NET-mediated physical barrier”, thereby increasing the contact of immune cytotoxic cells with tumor cells in living mice and sensitizing immune checkpoint therapy of primary colorectal cancer (CRC). Moreover, the deposition and light-controlled cargo release from systemically delivered AuPB@mPDA carriers in liver, the most frequent site of CRC metastasis, abolished NET-mediated capture of circulating tumor cells and hence metastatic seeding. Our findings indicate that the localized, light-regulated release of DNase I by photoactive carriers in the NIR-II window represent a translational route for immune-mediated tumor regression and metastasis inhibition.