Therapeutic transformation of a rhodium nanophotosensitizer into a tamoxifen-loaded targeted nano-drug for dual chemo-photodynamic therapy of ER-positive breast cancer.

Rhodium-based nanophotosensitizers have recently emerged as promising platforms for near-infrared (NIR)-activated photodynamic therapy (PDT). However, their therapeutic potential remains largely restricted to reactive oxygen species-mediated cytotoxicity, limiting their ability to address the complex molecular drivers of tumor progression. Here, we report the therapeutic transformation of a previously validated transferrin-targeted rhodium nanophotosensitizer into a dual-action nano-therapeutic by incorporating the selective estrogen receptor modulator tamoxifen within the mesoporous silica matrix. The resulting system enables a combined therapeutic strategy that integrates endocrine therapy and light-triggered photodynamic action, providing a targeted approach for estrogen receptor-positive (ER+) breast cancer. Structural and functional characterization confirmed efficient drug loading, preservation of photodynamic activity, and maintained targeting capability. In vitro studies demonstrated enhanced cytotoxic efficacy compared with single-modality treatments, while intracellular quantification by LC-MS verified sustained tamoxifen delivery. To elucidate the molecular mechanisms underlying therapeutic efficacy, quantitative SILAC-based proteomics revealed coordinated disruption of oxidative stress defense, calcium homeostasis, mitochondrial energy metabolism, and tumor proliferation pathways. These findings indicate that the combined therapy induces a multifaceted cellular response involving both ROS-mediated damage and modulation of endocrine signaling. Together, this work establishes a mechanistically informed dual-modality nano-drug that expands the therapeutic scope of rhodium nanophotosensitizers beyond conventional PDT, providing a new strategy for targeted treatment of ER-positive breast cancer.