# NIR-II biomimetic nanoplatform optogenetic CD274 editing of HNSCC immunogenicity for enhanced photoimmunotherapy

## TL;DR

This study presents a new photoimmunotherapy strategy using a biomimetic nanoplatform to edit the CD274 gene in head and neck cancer cells, enhancing immune response and treatment effectiveness.

## Contribution

A novel NIR-II optogenetic CRISPR/Cas9 system is developed to reprogram tumor immunogenicity by editing CD274 in HNSCC.

## Key findings

- ARPC nanoplatform induces CD274 gene editing and reduces its expression in HNSCC cells.
- NIR-II irradiation triggers immunogenic cell death and increases CD8+ T cell infiltration in tumors.
- The strategy shows potential for overcoming low immunogenicity in HNSCC treatment.

## Abstract

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.

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