A novel triple-modality MRI-photoacoustic-Raman nanoparticle (MPR) was developed to improve the delineation of brain tumor margins in living mice. The MPRs, composed of a gold core coated with a Raman-active layer and silica, were designed to accumulate in tumors due to the enhanced permeability and retention (EPR) effect. The particles were detected with high sensitivity (picomolar) by all three modalities in vitro and in vivo. Intravenous injection of MPRs into glioblastoma-bearing mice led to specific accumulation in tumors, enabling non-invasive tumor delineation. Raman imaging guided intra-operative tumor resection, and histological analysis confirmed accurate tumor margin delineation. The MPRs demonstrated excellent MRI contrast-to-noise ratio, high Photoacoustic signal intensity, and high sensitivity and specificity in Raman imaging. The particles remained in tumors for over a week, allowing pre- and intra-operative imaging. Histological validation confirmed MPR sequestration in tumors, with no accumulation in healthy brain tissue. The MPRs also enabled the visualization of invasive tumor margins and guided intra-operative tumor resection. The study highlights the potential of this triple-modality nanoparticle approach for more accurate brain tumor imaging and resection. The MPRs offer high sensitivity, deep tissue penetration, and the ability to detect tumor margins with high specificity. The particles are based on inert gold and silica, reducing cytotoxicity compared to other nanoparticles. The MPRs could also be useful for distinguishing tumor recurrence from non-specific treatment effects and for imaging other cancers with intrinsic EPR effects. The study demonstrates the potential of this approach for clinical translation, with ongoing development of endoscopic and intra-operative imaging devices.A novel triple-modality MRI-photoacoustic-Raman nanoparticle (MPR) was developed to improve the delineation of brain tumor margins in living mice. The MPRs, composed of a gold core coated with a Raman-active layer and silica, were designed to accumulate in tumors due to the enhanced permeability and retention (EPR) effect. The particles were detected with high sensitivity (picomolar) by all three modalities in vitro and in vivo. Intravenous injection of MPRs into glioblastoma-bearing mice led to specific accumulation in tumors, enabling non-invasive tumor delineation. Raman imaging guided intra-operative tumor resection, and histological analysis confirmed accurate tumor margin delineation. The MPRs demonstrated excellent MRI contrast-to-noise ratio, high Photoacoustic signal intensity, and high sensitivity and specificity in Raman imaging. The particles remained in tumors for over a week, allowing pre- and intra-operative imaging. Histological validation confirmed MPR sequestration in tumors, with no accumulation in healthy brain tissue. The MPRs also enabled the visualization of invasive tumor margins and guided intra-operative tumor resection. The study highlights the potential of this triple-modality nanoparticle approach for more accurate brain tumor imaging and resection. The MPRs offer high sensitivity, deep tissue penetration, and the ability to detect tumor margins with high specificity. The particles are based on inert gold and silica, reducing cytotoxicity compared to other nanoparticles. The MPRs could also be useful for distinguishing tumor recurrence from non-specific treatment effects and for imaging other cancers with intrinsic EPR effects. The study demonstrates the potential of this approach for clinical translation, with ongoing development of endoscopic and intra-operative imaging devices.