Tumor microenvironment responsive nano-PROTAC for BRD4 degradation enhanced cancer photo-immunotherapy

Proteolysis Targeting Chimeras (PROTAC) technology has garnered great attention due to its advantages in targeted protein degradation, promising its potential for treating malignant cancer. Nevertheless, the inherent drawbacks of PROTAC technology hinder its clinical translation. The integration of nanotechnology with PROTAC molecules to create nano-PROTACs for combined therapy offers a promising solution. Among the various cancer treatment methods, phototherapy is considered the optimal choice to integrate with specific PROTACs due to its proven effectiveness and non-invasive nature. Herein, a nano-PROTAC formulation (ARV@PEG-ICG) consisting of a phototherapeutic agent named indocyanine green functionalized polyethylene glycol (PEG-ICG) and a BRD4 degrader (ARV-825) was fabricated for cancer photo-immunotherapy. Activated by acidic tumor microenvironment (TME), ARV@PEG-ICG nanoparticles (NPs) will decompose rapidly for ARV delivery. PEG-ICG generated abundant ROS with laser irradiation, downregulating the expression of Bcl-xL and inducing the cleavage of PARP to stimulate cell apoptosis. Furthermore, the degradation of BRD4, a transcriptional cofactor, inhibited nitric oxide synthase (iNOS) generation to improve phototherapeutic efficacy. In a 4T1 breast tumor model, dying 4T1 cells released tumor associated antigens (TAAs) to serve as the immunogenic cell death (ICD) inducer, facilitating DC maturation and T cell activation and amplifying systemic immune response. The distant tumor growth can also be inhibited due to the activation of long-term immune response. Overall, the current study aims to combine typical PROTAC with functional nanomaterials to form nano-PROTAC with high performance for PROTAC delivery mediated cancer treatment.