Cation-Exchange Synthesized Zn-Doped Ag₂S Nanostructures for Photothermal and Photodynamic Therapies Across Breast Cancer Subtypes

Photothermal therapy (PTT) and photodynamic therapy (PDT) require nanostructures capable of efficiently converting red-light energy into both heat and reactive oxygen species (ROS). However, simultaneously achieving high photothermal conversion efficiency and strong ROS generation remains challenging. Here, we report zinc-doped Ag₂S (ZSS) nanostructures, synthesized via controlled cation exchange, in which Zn incorporation modulates the electronic structure of Ag₂S and improves charge separation, thereby enhancing red-light-activated PTT/PDT performance while preserving intrinsic biocompatibility. Among the series, ZSS(0.15) demonstrated optimized charge-carrier dynamics, a high photothermal conversion efficiency of 67.26%, and approximately four-fold higher singlet oxygen (¹O₂) generation relative to methylene blue under 660 nm irradiation. These physicochemical enhancements translated into potent therapeutic outcomes: in-vitro, ZSS(0.15) achieved an IC₅₀ of 15 µg/mL under irradiation, corresponding to approximately a 1.5-fold enhancement in cytotoxic potency compared to pristine Ag₂S, and induced apoptosis via activation of the p53/Bax/Caspase pathway. In-vivo, ZSS(0.15) with laser irradiation achieved ∼97% tumor volume suppression without systemic toxicity. Extending evaluation across multiple breast cancer cell lines representing distinct molecular subtypes further confirmed broad-spectrum in vitro efficacy. Altogether, these findings demonstrate that controlled Zn incorporation into Ag₂S effectively enhances red-light-driven photothermal conversion and ¹O₂ generation, establishing a rational materials strategy for improving synergistic PTT/PDT performance.