Radio-and photodynamic therapies are the first line of cancer treatments but suffer from poor light penetration and less radiation accumulation in soft tissues with high radiation toxicity. Therefore, a multifunctional nanoplatform with diagnosis-assisted synergistic radio-and photodynamic therapy and tools facilitating early prognosis are urgently needed to fight the war against cancer. Further, integrating cancer therapy with untargeted metabolomic analysis would collectively offer clinical pertinence through facilitating early diagnosis and prognosis. Here, we enriched scintillation of CeF 3 nanoparticles (NPs) through codoping Tb 3+ and Gd 3+ (CeF 3 :Gd 3+ ,Tb 3+ ) for viable clinical approach in the treatment of deep-seated tumors. The codoped CeF 3 :Gd 3+ ,Tb 3+ scintillating theranostic NPs were then coated with mesoporous silica, followed by loading with rose bengal (CGTS-RB) for later computed tomography (CT)-and magnetic resonance image (MRI)-guided X-ray stimulated synergistic radio-and photodynamic therapy (RT+XPDT) using low-dose, one-time X-ray irradiation. The results corroborated an efficient tumor regression with synergistic RT+XPDT relative to single RT. Global untargeted metabolome shifts highlighted the mechanism behind this efficient tumor regression using RT, and synergistic RT+XPDT treatment is due to the starvation of nonessential amino acids involved in protein and DNA synthesis and energy regulation pathways necessary for growth and progression. Our study also concluded that tumor and serum metabolites shift during disease progression and regression and serve as robust biomarkers for early assessment of disease state and prognosis. From our results, we propose that codoping is an effective and extendable technique to other materials for gaining high optical yield and multifunctionality and for use in diagnostic and therapeutic applications. Critically, the integration of multifunctional theranostic nanomedicines with metabolomics has excellent potential for the discovery of early metabolic biomarkers to aid in better clinical disease diagnosis and prognosis.

X-ray-induced photodynamic therapy (XPDT) is overwhelmingly superior in treating deep-seated cancers. However, limitations remain, owing to a combination of the poor scintillation performance of the nanoscintillator, low energy transfer efficiency of the therapeutic nanoplatform, and hypoxic environment presented in the tumor tissue. Collectively, these reduce the curative effect of XPDT. Here, we report a highly efficient, low-dose XPDT realized by systematic optimization from scintillation efficiency, nanoplatform structure, to therapeutic approach. We developed a biocompatible, codoped CaF 2 nanoscintillator that emitted sufficiently green radioluminescence that was bright enough to be seen by the naked eye. Using dendrimers as a framework, we built a nanoplatform featuring a dual-core−satellite architecture, which enabled both procedurally and spatially separate dual-loading of therapeutic agents. This strategy allowed for the fabrication of a combined XPDT and antiangiogenic therapy, resulting in a therapeutic system capable of simultaneous tumor attacks. After exposure to ultralow dose radiation, XPDT resulted in marked tumor reduction while the antiangiogenic drug effectively blocked tumor vascularization exacerbated by XPDT-mediated hypoxia, rendering a pronounced synergy effect. This system also showed high biosafety, as the agents adopted had been used clinically and both Ca and F elements were widespread in the human body. Taken together, the findings presented here provided a reference for the construction of complex, multiloading architecture in coordination with structural complexity and functional diversification. This work provided a safer and more robust application of the combined XPDT and antiangiogenesis in future clinical treatment settings.

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Distinctive upconversion or downshifting of lanthanide nanocrystals holds promise for biomedical and photonic applications. However, either process requires high-energy lasers at discrete wavelengths for excitation. Here we demonstrate that co-sensitization can break this limitation with ultrawide excitation bands. We achieve co-sensitization by employing Nd3+ and Ho3+ as the co-sensitizers with complementary absorptions from the ultraviolet to infrared region. Symmetric penta-layer core-shell nanostructure enables tunable fluorescence in the visible and the second near-infrared window when incorporating different activators (Er3+, Ho3+, Pr3+, and Tm3+). Transient spectra confirm the directional energy transfer from sensitizers to activators through the bridge of Yb3+. We validate the features of the nanocrystals for low-powered white light-emitting diode-mediated whole-body angiography of mice with a signal-to-noise ratio of 12.3 and excitation-regulated encryption. This co-sensitization strategy paves a new way in lanthanide nanocrystals for multidirectional photon conversion manipulation and excitation-bandwidth-regulated fluorescence applications.