GSH‐Responsive Semiconducting Polymer as a Nanotheranostic Platform for NIR‐II Imaging‐Guided Chemo‐Photothermal Therapy

The development of multifunctional nanotheranostic platforms with stimuli-responsive capabilities holds significant potential for enhancing cancer diagnosis and treatment. Herein, a glutathione (GSH)-responsive semiconducting polymer (SP) nanotheranostic system, SP/DOX-SS-PEG nanoparticles (NPs), is presented, designed for combined near-infrared II (NIR-II) fluorescence imaging (FI) and chemo-photothermal therapy. The amphiphilic SP (SP-SS-PEG) is synthesized through a multi-step reaction sequence, including Suzuki coupling, amidation, and thiol-disulfide exchange reactions, and subsequently encapsulates the anticancer drug doxorubicin (DOX) through self-assembly, resulting in the formation of GSH-responsive SP/DOX-SS-PEG NPs. These SP/DOX-SS-PEG NPs exhibit high photothermal stability and significant GSH-triggered DOX release. In vitro studies demonstrate that SP/DOX-SS-PEG NPs display enhanced cellular uptake and robust cytotoxicity against 4T1 cancer cells under 808 nm laser irradiation. Upon intravenous injection in tumor-bearing mice, NIR-II FI reveals efficient tumor accumulation and prolonged retention of the NPs. In vivo anti-tumor efficacy studies indicate that SP/DOX-SS-PEG NPs combined with 808 nm laser irradiation achieve the most significant inhibition of tumor growth, with minimal systemic toxicity. Taken together, these findings highlight the promising potential of SP/DOX-SS-PEG NPs as a multifunctional platform for precision cancer theranostics, integrating efficient NIR-II imaging, GSH-triggered drug release, and dual chemo-photothermal therapy.