Background <p>Radioluminescence imaging (RLI) using nanoscintillators offers great potential for biomedical applications, yet remains constrained by low quantum efficiency and the reliance of Cerenkov imaging on high-energy radionuclides. The rational design of core-shell nano-transducers overcomes these constraints by enhancing X-ray absorption and energy confinement, thereby enabling efficient γ-ray excited radioluminescence.</p> Results <p>We engineered NaGdF₄:15%Eu@NaLuF₄ core-shell nanoparticles as a superior nano-scintillator, designed to leverage Technetium-99m (^99mTc) as an ideal excitation source. The key advantage of our system lies in its ability to efficiently convert the low-energy electron emissions from ^99mTc into intense radioluminescence, completely bypassing the Cerenkov threshold and thus overcoming the key limitations of Cerenkov radiation. The optimized core-shell structure exhibited a radioluminescence intensity slope (k₁) of 10.9 × 10⁴ (p/s/cm²/sr)/MBq under ^99mTc excitation, representing a 110% enhancement over the core-only nanoparticles. This enhanced scintillation output was paired with a remarkable CT contrast slope (k₂) of 47.6 HU/(mg/mL), demonstrating superior X-ray absorption capability. Capitalizing on these attributes, when integrated with ^99mTc-sulfur colloid, this platform enabled background-free, multimodal SPECT/CT/RLI for high-contrast sentinel lymph node mapping and precise image-guided resection in murine models, the success of which was conclusively confirmed by histology.</p> Conclusion <p>This work presents a progressive optimization of lanthanide-based nanoparticles (LnNPs) scintillators, unveiling their structure-dependent radioluminescence properties for enhanced output efficiency. It thereby provides key insights into energy transfer processes within core-shell architectures and fundamentally expands the repertoire of applicable radionuclides for optical imaging.</p> Graphical Abstract <p></p>