<p>We present a novel activation mechanism of ultrasound (US)/magnetic resonance (MR) dual-modality imaging based on a ‘nano-in-nano encapsulation strategy’, where ultrasmall gadolinium oxide nanoparticles (Gd₂O₃ NPs) are encapsulated in CaCO₃ mineralized nanoparticles. Gd₂O₃ NP-encapsulated CaCO₃ mineralized nanoparticles (Gd₂O₃-MNPs) are designed to serve as a tumoral pH-activatable dual contrast imaging agent. The Gd₂O₃-MNPs were prepared by block copolymer-templated CaCO₃ mineralization in the presence of Ca²⁺ cations, CO₃²⁻ anions, and ultrasmall Gd₂O₃ NPs with positively charged surfaces. Transmission electron microscopy (TEM) and energy-dispersive X-ray (EDX) analyses confirmed the successful encapsulation of ultrasmall Gd₂O₃ NPs in the inner phase of CaCO₃ mineralized nanoparticles. At physiological pH (7.4), the Gd₂O₃-MNPs did not exhibit any noticeable contrast signals under an US field. In contrast, at tumoral pH (6.4), we found strong echogenic signals due to the generation of microsized CO₂ bubbles by the H⁺-triggered dissolution of CaCO₃ phases. In addition, at physiological pH (7.4), Gd₂O₃ NPs trapped in the CaCO₃ nanoparticle were shielded from the aqueous environments, which silenced their activity to enhance the water proton relaxation, whereas at tumoral pH (6.4), the Gd₂O₃-MNPs efficiently released Gd₂O₃ NPs into the aqueous phase, which resulted in a strong MR contrast enhancement. Through our proof-of-concept study, Gd₂O₃-MNPs may have potential as highly efficient activatable dual-modality contrast agents for collective US/MR imaging of various solid tumors.</p> Graphical abstract <p></p>