NIR‐II Absorbing Semiconducting Polymer‐Triggered Gene‐Directed Enzyme Prodrug Therapy for Cancer Treatment

Abstract Exploration of facile strategies for precise regulation of target gene expression remains highly challenging in the development of gene therapies. Especially, a stimuli‐responsive nanocarrier integrated with ability of noninvasive remote control for treating wide types of cancers is rarely developed. Herein, a NIR‐II absorbing semiconducting polymer (PBDTQ) is employed to remotely activate the heat‐inducible heat‐shock protein 70 (HSP70) promoter under laser irradiation, further realizing regulation of gene‐directed enzyme prodrug therapy (GDEPT) for cancer treatment in mild hyperthermia. In this multifunctional nanocomposite, the PBDTQ and double suicide gene plasmid (pSG) based on HSP70 promoter are incorporated into a lipid complex. Upon NIR‐II laser excitation, the mild photothermal effect (≈43 °C) generated from PBDTQ can cause the release of pSG and activation of HSP70 promoter, and then upregulate suicide gene expression triggered by the HSP70 promoter which can further convert the nontoxic prodrug into its cytotoxic metabolites. Therefore, this work demonstrates a universal NIR‐II laser‐triggered GDEPT using semiconducting polymers as the photothermal generator for cancer treatment with minimized collateral damage and nontargeted side effects.