This study presents a novel multimodal theranostic nanoplatform, QD@MSN-EPI-Au-PEG-Apt, for targeted chemo-radiotherapy in colorectal cancer (CRC). The nanoplatform consists of quantum dots (QDs), mesoporous silica nanoparticles (MSNs), and gold nanoparticles (Au NPs) coated with PEG and conjugated with EpCAM aptamers. QDs, coated with MSNs, were loaded with epirubicin (EPI) and capped with Au NPs to control drug release at acidic pH. The nanocarriers were characterized and found to have a size of ~65 nm. In vitro studies demonstrated selective cytotoxicity towards HT-29 cells compared to CHO cells, leading to reduced cell survival when combined with irradiation. In vivo studies in immunocompromised C57BL/6 mice showed enhanced anti-tumor effects and reduced side effects following chemo-radiotherapy, along with imaging capabilities using fluorescence (FLI), magnetic resonance (MRI), and computed tomography (CT) scans. The nanoplatform's success in targeted delivery and synergistic cytotoxicity highlights its potential for improved CRC theranostics.This study presents a novel multimodal theranostic nanoplatform, QD@MSN-EPI-Au-PEG-Apt, for targeted chemo-radiotherapy in colorectal cancer (CRC). The nanoplatform consists of quantum dots (QDs), mesoporous silica nanoparticles (MSNs), and gold nanoparticles (Au NPs) coated with PEG and conjugated with EpCAM aptamers. QDs, coated with MSNs, were loaded with epirubicin (EPI) and capped with Au NPs to control drug release at acidic pH. The nanocarriers were characterized and found to have a size of ~65 nm. In vitro studies demonstrated selective cytotoxicity towards HT-29 cells compared to CHO cells, leading to reduced cell survival when combined with irradiation. In vivo studies in immunocompromised C57BL/6 mice showed enhanced anti-tumor effects and reduced side effects following chemo-radiotherapy, along with imaging capabilities using fluorescence (FLI), magnetic resonance (MRI), and computed tomography (CT) scans. The nanoplatform's success in targeted delivery and synergistic cytotoxicity highlights its potential for improved CRC theranostics.