In-situ transformable photothermal targeting chimeras for spatiotemporally controllable protein degradation and combination immunotherapy for cancer

Targeted protein degradation (TPD) technology has been extensively exploited for cancer therapy. However, most current TPD approaches lack tissue specificity and are intended to induce on-target but also have off-tumor side effects. Moreover, simultaneous degradation of membrane and cytoplasmic proteins by a single TPD method remains a formidable challenge. To achieve tumor-specific degradation of immune-related membranes and intracellular proteins of interest, we rationally engineered a set of photothermal-targeting chimeras (PTTACs) by integrating a photothermal agent and a protein ligand. The PTTACs display superior photothermal conversion efficacy and protein binding affinity, can be readily loaded into acidity-activatable micellar nanoparticles, and can be specifically delivered into the tumor milieu for in situ self-assembly into two-dimensional nanosheets and selectively bind to proteins of interest (POIs). The combination of 808 nm laser irradiation with PTTAC nanosheets highly specifically degrades both the membrane (e.g., programmed death ligand 1 (PD-L1)) and intracellular (e.g., bromodomain protein 4 (BRD4)) proteins via the autophagy pathway. We demonstrated that the combination of the PTTACs-based nanoplatform with 808 nm laser irradiation markedly reduced 4T1 breast tumor growth and suppressed tumor metastasis by abolishing PD-L1 and BRD4 expression in tumor cells in vivo. Overall, this study provides a robust strategy for spatiotemporally confined protein degradation and combination immunotherapy of solid tumors.