Semiconducting polymer nanomanipulators for thermal sensitization and metastasis-inhibited synergistic cancer therapy

Manipulation of intracellular protein expression is a promising cancer therapeutic approach; however, traditional strategies relying on nonspecific molecular drugs often suffer from limited therapeutic benefits and off-target adverse events. Here, we report a semiconducting polymer nanomanipulator (SPNm) that can photothermally manipulate intracellular protein expression to synergize with its own function of second near-infrared (NIR-II) photothermal therapy (PTT) for thermal sensitization and metastasis-inhibited cancer therapy. SPNm comprises an NIR-II absorbing semiconducting polymer core as a photothermal transduction agent and a lysine-specific histone demethylase 3 A (KDM3A) inhibitor as a downstream effector protein expression manipulator, which are encapsulated into a thermo-responsive lipid shell. Upon 1064 nm laser irradiation, SPNm mediates the photothermal effect to melt the lipid shell for on-demand release of the KDM3A inhibitor to inhibit the demethylation function of KDM3A to upregulate the level of di-methylation of histone H3 lysine 9 (H3K9me2), and in turn simultaneously downregulate the expression of heat-shock protein 90 (HSP90) and cancer cell metastasis-related proteins, consequently inhibiting the thermotolerance response and metastasis of cancer cells. Thus, a single treatment of SPNm-mediated two-step NIR-II phototherapy achieves efficient tumor growth suppression at an unprecedented photothermal ablation depth (1 cm) and lung metastasis inhibition. Therefore, this study provides a promising thermal-controlled strategy to synergize phototherapeutics with protein expression manipulation for enhanced cancer treatment.