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, current TPD approaches suffer from two major limitations that the lack of tissue and subcellular specificity for precise localization, and insufficient postdegradation benefits due to their reliance on single traditional pathway regulation. To achieve tumor-specific degradation of immune-related membrane 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. The combination of 808 nm laser irradiation with PTTAC nanosheets highly specifically degrades both the membrane (e.g., PD-L1) and intracellular (e.g., BRD4) proteins via the autophagy pathway. The PTTAC-based nanoplatform combination markedly reduced 4T1 breast tumor growth upon 808 nm laser irradiation and suppressed metastasis by durably abolishing PD-L1 and BRD4 expression, outperforming single-pathway therapy. Overall, this study provides a robust strategy for spatiotemporally confined all-protein degradation and combination immunotherapy of solid tumors.