Ultrasound-triggered transformable DNA nanomedicine improves cascade delivery for enhanced antitumor efficacy

Conventional nanocarriers with fixed physicochemical properties struggle to simultaneously address the conflicting demands of tumor tissue targeting, cellular uptake, and organelle-specific delivery. To overcome this limitation, we developed an intelligent nanomedicine, designated Ca-pHis-DNA, through coordination-driven self-assembly of polyhistidine (pHis)-modified DNA with calcium ions (Ca²⁺). Under ultrasound (US) irradiation, Ca-pHis-DNA undergoes a controllable morphological transition from spherical nanoparticles to elongated fibrous assemblies. Additionally, in the acidic tumor microenvironment (TME), protonation of the histidine residues induces a shift toward positive surface charge, further enhancing cellular internalization and endo/lysosomal escape. The synergistic effects of these stimuli prolong tumor retention, enhance cellular uptake, promote endosomal escape, and enable mitochondria targeting, thereby achieving cascade drug delivery. Furthermore, US stimulation induces calcium overload and reactive oxygen species (ROS) generation, synergistically enhancing therapeutic efficacy. This dual pH/US-responsive deformable nanomedicine provides a potent and safe strategy for solid tumor therapy. • A smart nanoparticle changes shape and charge in response to ultrasound and tumor acidity. • Ultrasound transforms round particles into fibers for deeper tumor penetration. • In acidic environment, Ca-pHis-DNA becomes positively charged to escape compartments. • Ca-pHis-DNA precisely targets mitochondria, disrupting their function and causing cell death. • This strategy offers a potent and safe cascade delivery system for cancer therapy.