PD-L1 Blockade Peptide-Modified Polymeric Nanoparticles for Oxygen-Independent-Based Hypoxic Tumor Photo/Thermodynamic Immunotherapy.

Distant metastasis of malignant tumors is considered to be the main culprit for the failure of current antitumor treatments. Conventional single treatments often exhibit limited efficacy in inhibiting tumor metastasis. Therefore, there is a growing interest in developing collaborative antitumor strategies based on photothermal therapy (PTT) and free-radical-generated photodynamic therapy (PDT), especially utilizing oxygen-independent nanoplatforms, to address this challenge. Such antitumor strategies can enhance the therapeutic outcomes by ensuring the cytotoxicity of free radicals even in the hypoxic tumor microenvironment, thereby improving the effective suppression of primary tumors. Additionally, these approaches can stimulate the production of tumor-associated antigens and amplify the immunogenic cell death (ICD) effects, potentially feasible for enhancing the therapeutic outcomes of immunotherapy. Herein, we fabricated a functional nanosystem that co-loads IR780 and 2,2'-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH) to realize PTT-triggered thermodynamic combination therapy via the oxygen-independent pathway for the elimination of primary tumors. Furthermore, the nanocomposites were surface-decorated with a predesigned complex peptide (PLGVRGC-anti-PD-L1 peptide, MMP-sensitive), which facilitated the immunotherapy targeting distant tumors. Through the specific recognition of matrix metalloproteinase (MMP), the sensitive segment on the obtained aNC@IR780A was cleaved. As a result, the freed anti-PD-L1 peptide effectively blocked immune checkpoints, leading to the infiltration and activation of T cells (CTLs). This nanosystem was proven to be effective at inhibiting both primary tumors and distant tumors, providing a promising combination strategy for tumor PTT/TDT/immunotherapy.