Carrier-Free Nano-Proteolysis Targeting Chimeras Enable Selective Protein Degradation and Enhance Photoimmunometabolic Therapy against Lung Adenocarcinoma

The suboptimal efficacy of immunotherapy is closely associated with the immunosuppressive tumor microenvironment, especially the overexpression of bromodomain-containing protein 4 (BRD4) and the accumulation of immunosuppressive adenosine. This study aimed to develop carrier-free nanoparticles (MNC NPs) by integrating a BRD4-targeting proteolysis-targeting chimera (PROTAC), an adenosine A2A receptor (A2AR) antagonist, and a photosensitizer to enhance the efficacy of immunotherapy. Clinical data from the Gene Expression Omnibus and patient samples highlighted the therapeutic potential of simultaneously targeting BRD4 and A2AR in lung adenocarcinoma. The prepared NPs exhibited high accumulation of PROTACs in tumors, leading to selective degradation of BRD4 and a reduction in programmed cell death ligand 1 (PD-L1), thereby alleviating immune resistance. Concurrently, the incorporated antagonist effectively blocked the adenosine-A2AR axis, reversing adenosine-mediated immunosuppression. Furthermore, photosensitizers initiated photodynamic therapy, facilitating tumor ablation and inducing immunogenic cell death to promote immune activation. <i>In vivo</i> studies in a murine lung cancer model demonstrated potent suppression of primary, distant, and metastatic tumors. This study underscored the potential of nano-PROTACs to synergistically integrate protein-selective degradation, immunometabolic reprogramming, and photodynamic immunotherapy, offering a promising strategy for lung adenocarcinoma treatment.