NIR II‐Guided Photoactivatable Silencing Polyplex Boosts Cancer Immunotherapy

ABSTRACT Photodynamic therapy (PDT) triggers immunogenic cell death (ICD) within the tumor microenvironment, consequently enhancing tumor immunotherapy. However, the maximum absorption wavelengths of first and second‐generation PDT photosensitizers limit the penetration depth of therapeutics, resulting in insufficient anti‐tumor outcomes. This study reports a custom‐designed polymer, PTSQ, which exhibits significant absorption in the near‐infrared region (NIR) window and fluorescence emission spectra within the NIR II range, demonstrating excellent PDT efficiency. Additionally, PTSQ self‐assembles into nanomicelles, exhibiting outstanding siRNA delivery. To further enhance tumor immunotherapy, we introduce an immune checkpoint blockade strategy and prepared PTSQ/siPD‐L1 complexes. We present a novel approach to tumor treatment by combining NIR light‐activated PDT and ICD to enhance siPD‐L1 therapy. At the cellular level, PTSQ/siPD‐L1 complexes exhibit potent induction of ICD while concurrently suppressing PD‐L1 gene expression. In vivo, these complexes significantly impede the growth of CT26, 4T1, and patient‐derived xenograft (PDX) tumors. This effect is achieved by promoting in situ ICD, which reverses tumor environment and activates immune cells in tumors and spleens, including T cells, dendritic cells (DCs), and macrophages. Overall, this study offers insights for the development of NIR II‐guided cancer immunotherapy and underscores the efficacy of PDT in conjunction with checkpoint blockade for cancer treatment.