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 thermo-tolerance 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 treat-ment.(c) 2022 Elsevier Ltd. All rights reserved.

Automated summary

This study reports a semiconducting polymer nanomanipulator (SPNm) that can manipulate intracellular protein expression through photothermal effect, resulting in suppression of tumor growth and inhibition of cancer cell metastasis. This novel nanomanipulator holds great potential for cancer therapeutics.