NIR-II Biomimetic Nanoplatform Optogenetic CD274 Editing of HNSCC Immunogenicity for Enhanced Photoimmunotherapy

Although immunotherapy has achieved impressive breakthroughs in head and neck squamous cell carcinoma (HNSCC), it still encounters significant challenges such as the intrinsic low immunogenicity microenvironment and limited T cell infiltration. In this work, we aimed to edit the CD274 gene of HNSCC cells by optogenetics with second near-infrared (NIR-II) light, thereby reducing the CD274 expression and improving the efficacy of photo-immunogenic therapy. Specifically, a biomimetic nanoplatform (ARPC) was established by using an α-LDLR (low density lipoprotein receptor antibody) engineered red blood cell membrane (RBCm) to deliver NIR-II photothermal polymers and CRISPR/Cas9 plasmids. After intravenous injection into HNSCC-bearing mice, ARPC can induce heat stress upon NIR-II laser irradiation at tumor sites, causing the upregulation of Hsp70 to trigger CRISPR/Cas9 for CD274 editing. Moreover, the mild photothermal therapeutic effect of ARPC simultaneously induced immunogenic cell death in tumor cells for enhancing CD8+ T cell infiltration and proliferation, and thereby leading to photoimmunotherapy. This study provides an NIR-II optogenetic CRISPR/Cas9 CD274 for editing reprogrammed photo-immunogenic therapy strategy, showing great clinical potential for overcoming the low immunogenicity of HNSCC.