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

Abstract 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.