Tumor-penetrating nanoplatform with ultrasound “unlocking” for cascade synergistic therapy and visual feedback under hypoxia

BACKGROUND: Combined therapy based on the effects of cascade reactions of nanoplatforms to combat specific solid tumor microenvironments is considered a cancer treatment strategy with transformative clinical value. Unfortunately, an insufficient O(2) supply and the lack of a visual indication hinder further applications of most nanoplatforms for solid tumor therapy. RESULTS: A visualizable nanoplatform of liposome nanoparticles loaded with GOD, H(Gd), and PFP and grafted with the peptide tLyP-1, named (tLyP-1)H(Gd)-GOD@PFP, was constructed. The double-domain peptide tLyP-1 was used to specifically target and penetrate the tumor cells; then, US imaging, starvation therapy and sonodynamic therapy (SDT) were then achieved by the ultrasound (US)-activated cavitation effect under the guidance of MR/PA imaging. GOD not only deprived the glucose for starvation therapy but also produced H(2)O(2), which in coordination with (1)O(2) produced by H(Gd), enable the effects of SDT to achieve a synergistic therapeutic effect. Moreover, the synergistic therapy was enhanced by O(2) from PFP and low-intensity focused ultrasound (LIFU)-accelerated redox effects of the GOD. The present study demonstrated that the nanoplatform could generate a 3.3-fold increase in ROS, produce a 1.5-fold increase in the maximum rate of redox reactions and a 2.3-fold increase in the O(2) supply in vitro, and achieve significant tumor inhibition in vivo. CONCLUSION: We present a visualizable nanoplatform with tumor-penetrating ability that can be unlocked by US to overcome the current treatment problems by improving the controllability of the O(2) supply, which ultimately synergistically enhanced cascade therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-023-01765-x.