Cancer-targeted pro-theranostic bi-metallic organo-coordination nanoparticles

<b>Rationale:</b> Cancer remains a leading cause of mortality, with aggressive, treatment-resistant tumors posing significant challenges. Current combination therapies and imaging approaches often fail due to disparate pharmacokinetics and difficulties correlating drug delivery with therapeutic response. <b>Methods:</b> In this study, we developed radionuclide-activatable theranostic nanoparticles (NPs) comprising folate receptor-targeted bimetallic organo-nanoparticles (Gd-Ti-FA-TA NPs). Polyvalent tannic acid was used to coordinate titanium (Ti), a reactive oxygen species (ROS)-generating catalyst, gadolinium (Gd), a magnetic resonance imaging (MRI) contrast agent, and cypate, a near-infrared fluorescent dye. <b>Results:</b> The NPs exhibited higher magnetic field-dependent relaxivities (<i>r</i> ₁ = 20.8 mM⁻¹s⁻¹, <i>r</i> ₂ = 72.1 mM⁻¹s⁻¹) than Gd-DTPA (<i>r</i> ₁ = 4.8 mM⁻¹s⁻¹, <i>r</i> ₂ = 4.9 mM⁻¹s⁻¹) on a 3 T MRI scanner. Tannic acid coordination reduced the Ti band gap from 3.3 eV in TiO₂ NPs to 2.0 eV, tripling ROS generation under UV light exposure. In breast cancer models (4T1 and PyMT-Bo1), Cerenkov radiating radiopharmaceuticals activated Gd-Ti-FA-TA NPs <i>in vitro</i> and <i>in vivo</i>, generating cytotoxic ROS to inhibit tumor cell viability and prevent tumor progression. <i>In vivo</i>, the NPs selectively accumulated in 4T1 tumors and enhanced both T₁ and T₂ MRI contrast, highlighting a strategy to locally activate cytotoxic ROS generation with radiopharmaceuticals for cancer treatment, utilizing cross-modality PET/MRI and optical imaging for shallow and deep tissue visualization. <b>Conclusion:</b> The integrated nanoplatform allows direct imaging of drug delivery, providing guidance for the optimal timeline to activate therapeutic effects of pro-theranostic NPs via external triggers such as radionuclide-stimulated dynamic treatment.